Methods and devices for endovascular therapy

ABSTRACT

The present invention provides methods and devices for treating endovascular disease. Vibrational energy is delivered to change compliance and increase permeability at the treatment area. To improve clinical outcomes, one or more therapeutic drugs may be delivered to the treatment area.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/278,353, of Wallace, filed on Oct. 6, 2009, and is acontinuation-in-part of application Ser. No. 14/164,512 filed Jan. 27,2014, which is a continuation-in-part of application Ser. No. 13/962,646filled on Aug. 8, 2013, which is a continuation-in-part of applicationSer. No. 13/625,405 filled on Sep. 24, 2012, which is acontinuation-in-part of application Ser. No. 13/438,221 filled on Apr.3, 2012, now abandoned, which is a continuation-in-part of applicationSer. No. 13/134,470 filled on Jun. 8, 2011, which is acontinuation-in-part of application Ser. No. 12/930,415 filed Jan. 6,2011, now abandoned, which is a continuation-in-part of application Ser.No. 12/925,495 filed Oct. 22, 2010, which is a continuation-in-part ofapplication Ser. No. 12/807,129, filed Aug. 27, 2010, now abandoned,which is in turn continuation-in-part of application Ser. No.12/661,853, filed Mar. 25, 2010 now abandoned.

TECHNICAL FIELD OF THE INVENTION

The present invention is related to medical devices and methods. Morespecifically, the invention is related to endovascular devices andmethods for the treatment of stenosis, inhibiting restenosis, plaqueremoval, thrombus removal, crossing totally occluded arteries or veins,the treatment of heart valves, and the treatment of vulnerable plaqueand the removal of tissue, blood clots and liquids from the human body.Treatment of these diseases may be performed with or without the use oftherapeutic drugs.

BACKGROUND

Atherosclerosis and its consequences, including arterial stenosis,venous stenosis and hypertension, represent a major health problem bothin the U.S. and throughout the world. A common treatment for arterialstenosis and occlusions involves balloon angioplasty, more specificallypercutaneous transluminal balloon angioplasty (PTA), a procedure inwhich a balloon catheter is advanced through the artery to the stenoticor occluded site and expanded there to widen the artery. A stent is alsocommonly placed at the stenotic site for the purpose of maintainingpatency of the newly opened artery. Angioplasty and stent implantation,however, often are of limited long term effectiveness due to restenosisand reocclusion. In a study of intracoronary stenting, for example,restenosis was observed to occur over the long term in 15% to 30% ofpatients (Serruys et al., 1994, N. Engl. J. Med., 331:489).

The use of therapeutic agents with presumed antistenotic or anti-intimalthickening activity has been combined with stent-based therapy.Drug-eluting stents that deliver a drug such as Sirolimus or Paclitaxelhave been used most frequently in the hope that a slowly eluting drugwill impede restenosis. In another recent approach, balloon catheterswith drug eluting balloons have been tried for restenosis prevention.While these approaches have met with some success, the restenosisproblem is far from solved, as drug eluting stents and balloons have hadmixed results in clinical studies.

Yet another approach to treating vascular stenosis and preventingrestenosis involves administering a therapeutic agent at the stenosissite, either alone or in conjunction with a conventional endovascularinterventional procedure such as angioplasty or venoplasty, with orwithout stenting. In this approach a therapeutic agent is delivered tothe stenotic site through a catheter. Numerous therapeutic agents havebeen examined for their anti-proliferative effects, and some of whichhave shown some effectiveness with regard to reducing intimalhyperplasia. These agents, by way of example, include heparin andheparin fragments, angiotensin converting enzyme (ACE) inhibitors,angiopeptin, cyclosporin A, goat-anti-rabbit PDGF antibody, terbinafine,trapidil, tranilast, interferon-gamma, rapamycin, corticosteroids,fusion toxins, antisense oligonucleotides, and gene vectors. Othernon-chemical approaches have also been tried, such as ionizingradiation.

While holding considerable promise, the methods and devices fordelivering antistenotic therapeutic agents to blood vessel wall tissueare as yet not fully satisfactory. Absorption of the therapeutic agentinto the blood vessel wall, for example, represents a significantchallenge. Furthermore, it would be advantageous to incorporate orcoordinate delivery of a therapeutic with an angioplasty, venoplastyand/or stent placement procedure. Any attractive new methods or devicesfor therapeutic agent delivery would need to be safe, effective, andrelatively simple to perform. At least some of these objectives are metby the embodiments of the invention as provided herein.

A need exists for devices and methods that allow ultrasound energy to bemore evenly applied to the vessel wall, and to induce homogeneouscellular changes to increase vessel permeability, so that therapeuticdrugs can be more effective. Ideally, such devices would providesufficient delivery of ultrasound energy to the surrounding tissue(either to small or large vessels), and consequently increase vesseldrug uptake. While such devices should provide necessary ultrasoundenergy, they also should avoid and prevent vascular injures. Also,dissolving endovascular blood clots maybe more efficient when ultrasoundenergy is delivered uniformly to the treatment area. At least some ofthese objectives will be met by the present invention.

BRIEF SUMMARY OF THE INVENTION

The scope of the present invention is best defined by the appendedclaims. In certain instances, detailed descriptions of ultrasoundphysics, well-known devices, compositions, components, mechanisms andmethods are omitted so as to not obscure the description of the presentinvention with unnecessary details.

The inventive technology described herein provides new methods anddevices to improve the treatment of vascular stenosis and re-stenosisusing ultrasound technology to enhance delivery of therapeutic agentsdirectly to a targeted therapeutic site, such as a stenotic site on anarterial or vein wall. Aspects of the anti-stenotic treatmentmethodology may include ultrasound-enhanced delivery of therapeuticagents to a stenotic site to reduce plaque and to increase the patencyof the afflicted vessel as stand-alone or first treatment optionsperformed without other physical interventions directed towardincreasing vessel patency, or such treatments may done in conjunctionwith other interventional approaches, such as treatment of a sitepreviously treated or contemporaneously treated to inhibit or preventrestenosis.

Embodiments of the invention include a method and devices for treatingstenosis or inhibiting restenosis in an artery or vein by delivering atherapeutic agent into the artery or vein and enhancing absorption ofthe therapeutic agent into a wall of the artery or vein using ultrasoundenergy. Such method includes advancing a distal end of a combinedultrasound/drug delivery catheter to an area of stenosis or restenosisin an artery or vein; delivering a stenosis inhibiting therapeutic agentinto the artery or vein from the ultrasound/drug delivery catheter; andactivating the ultrasound catheter to emit ultrasound energy whiledelivering the therapeutic agent.

Another embodiment of the present invention includes a method anddevices for treating or inhibiting restenosis in an artery or vein byfirst delivering ultrasound energy to the vessel wall and exposing thevessel wall to ultrasound energy using an ultrasound catheter. Afterexposing the vessel wall to ultrasound energy, a stenosis inhibitingtherapeutic agent is delivered into the artery or vein. Delivery of sucha therapeutic agent can be accomplished with the same device or througha separate drug delivery catheter. A separate catheter to delivertherapeutic drug may be an ultrasound energy catheter or any other drugdelivery catheter.

Alternatively, the present invention also includes a method and devicesfor treating or inhibiting restenosis in an artery or vein by deliveringultrasound energy from an external ultrasound energy source from outsideof the body, through the skin (also known as transcutaneous approach).After exposing the vessel wall to ultrasound energy from the externalsource, a stenosis inhibiting therapeutic agent is delivered into theartery or vein. Delivery of such therapeutic agent can be accomplishedby using an endovascular drug delivery catheter.

These methods and devices for treating stenosis or inhibiting restenosisare such that the delivery of the ultrasonic energy either from anexternal ultrasound energy source or from an endovascular ultrasounddevice causes vasodilatation within vessel wall. In typical embodimentsof the method, the therapeutic agent is delivered from the ultrasounddrug delivery catheter at or near the distal end, and activating theultrasound drug delivery catheter converts the therapeutic agent intodroplets.

In various embodiments, the therapeutic agent may be dispersed at aconstant rate or a variable rate. In some embodiments, the therapeuticagent is delivered from a plurality of outlet ports that are arrayedaround the distal end of the ultrasound catheter. In other embodiments,the therapeutic agent may be delivered from a perfusion porous balloon,a balloon coated with the therapeutic agent or from an expandable meshcoated with the therapeutic agent located at the distal end of theultrasound drug delivery catheter. In still other embodiments, thetherapeutic agent is delivered in radial fashion through at least one ofthe outlet ports located in the distal tip of the ultrasound drugdelivery catheter or outlet ports located on the ultrasound catheterbody proximal to the distal tip. In another embodiment, the therapeuticagent can be delivered following delivery of ultrasound energy to thevessel wall in any desirable fashion, utilizing the same or differentultrasound catheter or employing these methods using any conventionaldrug delivery catheter.

Some embodiments of the method and devices for treating stenosis orinhibiting restenosis further include delivering an irrigation fluidthrough the ultrasound catheter during the ultrasound catheteractivation. In some of these embodiments, the irrigation fluid and thetherapeutic agent are delivered together in a mixture; in otherembodiments, the irrigation fluid is delivered separately from thetherapeutic agent. In these latter embodiments, the method may includeintroducing an irrigation fluid via one or more outlet ports on theultrasound/drug delivery catheter that are separate from one or moretherapeutic agent outlet ports.

The scopes of the embodiments of the method and devices include theapplication of any therapeutic agent to a target site, such agentsconsidered to be medically beneficial to the patient being treated, andexamples of such agents are provided in the detailed description. Thetherapeutic agent or agents may be in any of the following forms:liquid, powder, particle, microbubbles, microspheres, nanospheres,liposomes and combinations thereof. The therapeutic agent(s) may bedelivered directly to the treatment area in a solution-liquid form orcan be placed on the surface of other devices, such as stents orballoons, and delivered to the treatment area.

Embodiments of the method and devices for treating stenosis orinhibiting restenosis may further include repositioning or moving theultrasound drug delivery catheter during ultrasound energy activationand a therapeutic agent delivery to further enhance drug delivery.

Embodiments of the method and devices for treating stenosis orinhibiting restenosis may further include a blood flow protectiondevice(s), such as balloon devices that are independent from ultrasounddelivery device or coupled to the ultrasound catheter, within the arteryor vein to prevent the therapeutic agent from flowing down stream. Insuch embodiments, expanding the blood flow protection device includesexpanding it in at least one of the locations of distal to theultrasound catheter distal tip or proximal to the ultrasound catheterdistal tip. These method embodiments may further include removing thetherapeutic drug trapped by the blood flow protection device(s) from thebody.

Embodiments according to the present invention for treating stenosis orinhibiting restenosis may further include delivering therapeutic agentafter the delivery of ultrasound energy: first exposing the treatmentarea to ultrasound energy either from an external ultrasound source(such as an ultrasound transducer) or from an endovascular ultrasoundcatheter, and after ultrasound, exposing to the vessel wall, arteriallyor venously delivering the therapeutic agent to the treatment area.

In some embodiments of the present invention for treating stenosis orinhibiting restenosis, advancing the ultrasound drug delivery catheterincludes advancing it in a manner selected from monorail, over-the-wire,and without the use of a guidewire. In various embodiments, theultrasound catheter can operate in continuous mode, pulse mode and acombination continuous/pulse mode, and in some embodiments theultrasound energy can be modulated. Modulation of ultrasound energy mayinclude modulation of voltage, current, frequency or pulse parameterssuch as ultrasound energy ON/OFF time or any combination of all. Instill other embodiments, advancing the ultrasound/drug delivery cathetermay include contacting the wall of the blood vessel with the catheter.

Some embodiments of the present invention for treating stenosis orinhibiting restenosis further include performing an angioplasty orvenoplasty procedure before, during or after delivery of the therapeuticagent and ultrasound energy, wherein the angioplasty or venoplastyprocedure can be balloon angioplasty or venoplasty, stent placement,atherectomy, laser angioplasty or venoplasty, ultrasound angioplasty orvenoplasty, cryoplasty, or a combination of these procedures. In variousembodiments, performing the angioplasty or venoplasty procedure includesadvancing a balloon device over a guidewire to the area of stenosis orrestenosis in the artery or vein, wherein the combined ultrasound drugdelivery catheter is advanced over the same guidewire.

In various other embodiments of the present invention, treating stenosisor inhibiting restenosis further include performing an angioplasty orvenoplasty procedure before, during or after delivery of the ultrasoundenergy and delivery of therapeutic agent is performed separately fromdelivering ultrasound energy, either during or after deliveringultrasound energy.

In another aspect, the present invention provides a method for treatingstenosis and inhibiting restenosis in an artery or vein by dilating theartery or vein, delivering a therapeutic agent to the artery or vein,and at the same time enhancing absorption of the therapeutic agent usingultrasound energy. In this aspect, the method may include advancing adistal portion of a combined dilation, ultrasound, drug deliverycatheter to an area of stenosis or restenosis in an artery or vein;expanding an arterial dilator of the catheter to dilate the artery orvein at the area of stenosis or restenosis; delivering a stenosisinhibiting therapeutic agent into the artery or vein through thecatheter; and activating the catheter to emit ultrasound energy whiledelivering the therapeutic agent

In still another aspect, the present invention provides a method anddevices for treating stenosis and inhibiting restenosis in an artery orvein by delivering a therapeutic agent to the artery or vein andenhancing absorption of the therapeutic agent using ultrasound energy.In this aspect, the method may include advancing a distal portion of acombined ultrasound/drug delivery catheter to an area of stenosis orrestenosis in an artery or vein; expanding an expandable member, such asa balloon, coupled with the catheter at least one of distal or proximalto a drug delivery portion of the catheter, to prevent the therapeuticagent from flowing at least one of proximally or distally beyond theexpandable member; delivering a stenosis inhibiting therapeutic agentinto the artery or vein through the catheter; and activating thecatheter to emit ultrasound energy while delivering the therapeuticagent. In various of these particular embodiments, expanding theexpandable member includes expanding a member either distal to orproximal to the drug delivery portion of the catheter. In someembodiments, expanding the expandable member includes expanding twoexpandable members, one distal to and one proximal to the drug deliveryportion of the catheter.

In still another aspect, the present invention provides a method anddevices of treating vulnerable plaque that includes introducing anultrasound dispersed therapeutic agent to a treatment area; andactivating ultrasound energy to cause passage of the therapeutic druginto the vessel wall.

In still another aspect, the invention provides a method and devices fortreating stenosis or inhibiting restenosis in a totally occluded arteryor vein by delivering a therapeutic agent into the artery or vein andenhancing absorption of the therapeutic agent into a wall of the arteryor vein using ultrasound energy. This embodiment may include advancing adistal end of a combined ultrasound/drug delivery catheter to an area ofa totally occluded artery or vein; delivering a stenosis inhibitingtherapeutic agent into the artery or vein from the ultrasound/drugdelivery catheter; and activating the ultrasound catheter to emitultrasound energy while delivering the therapeutic agent. In some ofthese embodiments, advancing a distal end of a combined ultrasound/drugdelivery catheter to an area of stenosis or restenosis in an artery orvein is performed without ablation or removal of material. In otherembodiments, treating stenosis or inhibiting restenosis in an artery orvain by delivering a therapeutic agent into the artery or vain andenhancing absorption of the therapeutic agent into a wall of the arteryor vain using ultrasound energy further includes ablation or removal ofmaterial.

Embodiments of the inventive therapeutic methodology will now besummarized with reference to an approach to antistenotic treatment ofblood vessels more broadly, whether the treatment site is beingsubjected to a first treatment, a repeat treatment following any otherantistenotic treatment, a follow up treatment to prevent or inhibitrestenosis following a previous antistenotic treatment of any kind, andwhether the treatment site is totally occluded, partially occluded,experiencing in-stent occlusion, vein graft occlusion, or artificialgraft occlusion, or diagnosed as being vulnerable to occlusion, or anycombination thereof.

Embodiments of the inventive methods and devices provided herein relateto approaches to antistenotic treatment at a target site in a bloodvessel, a vein or an artery, for example, by using ultrasound energy toenhance delivery of a therapeutic agent. The site of treatment may be asite that has not been previously treated, the treatment embodimentthereby being a first therapeutic intervention, or the treatment sitemay have been treated before by another interventional method, or evenby the present inventive method (i.e., a repeat treatment). In someembodiments of the method, the ultrasound-enhanced therapeutic agent isapplied in close temporal conjunction with other interventional methods,such as angioplasty or venoplasty. In various embodiments the method maybe applied to vessels with a range of stenosis or plaque buildup,ranging from mild occlusion to total occlusion. In other embodiments,the method may be applied to treatment sites in order to impede orprevent restenosis following an earlier treatment. In still otherembodiments, the method may be applied to sites identified as beingvulnerable to stenotic processes. The scope of embodiments of the methodincludes the application of any therapeutic agent to a target site, suchagents considered to be medically beneficial to the patient beingtreated.

Embodiments of the method and devices of antistenotic treatment includepositioning a distal end of a combined ultrasound drug delivery catheterproximate the treatment site in a blood vessel. This positioning of thecatheter proximate the site may be accomplished without ablating orremoving any plaque material that may be present. Embodiments of themethod further include delivering a fluid formulation including atherapeutic agent to the site from the ultrasound drug deliverycatheter; and emitting ultrasound energy from the ultrasound catheterwhile delivering the therapeutic agent. In some embodiments of themethod, a dilator may also be positioned at the treatment site anddilated, such dilation increasing the efficiency and consistency ofultrasound delivery to areas of the internal vessel surface at thetreatment site. While, as noted above, some embodiments of the method donot include direct physical or energy delivery attack on plaque, otherembodiments may include ablating, removing, or compressing plaquematerial at the treatment site.

With regard to aspects of the delivery of ultrasound energy to thetarget site, the ultrasound energy source (such as an externalultrasound transducer or endovascular ultrasound catheter or ultrasounddrug delivery catheter) may be operated in a continuous mode, a pulsemode, or in any combination or sequence thereof; further the ultrasoundenergy may be modulated. In general, the emitted ultrasonic energy issufficient to cause vasodilatation of the blood vessel and/orsonoporation within cells of the vessel wall proximate the target site,preferably, without causing vascular damage. Alternatively, ultrasoundenergy may be delivered separately from delivering therapeutic agentusing the same device or a different device. A different conventionaldrug delivery catheter may be used together with ultrasound deliverycatheter.

As noted above, some embodiments may include repeated applications, ormultiple applications at the same site, or at another portion of alarger treatment site. Thus, for example, embodiments of the method mayinclude repositioning the ultrasound drug delivery catheter; andrepeating the step of emitting ultrasonic energy. Positioning theultrasound drug delivery catheter at the target site may includepositioning the catheter nearby the target site, or it may includecontacting the vessel wall at the site. In some embodiments, thecontacting may be optimized by dilation of the treatment site, so as tooptimize and make uniform a therapeutically effective contact betweenthe ultrasound catheter and the target tissue.

Some embodiments include advancing an ultrasound/drug delivery catheterto the treatment site either prior to or in conjunction with appropriatepositioning of the catheter for treatment of the site. Advancing thecatheter may be accomplished by conventional approaches either with orwithout a guidewire. Guidewire-assisted methods may include anyapproach, such as over-the-wire, or monorail deployment.

Some embodiments of the method and devices of antistenotic treatment mayfurther include expanding a first blood flow prevention member coupledto the catheter at a site proximate the drug delivery portion of thecatheter to a degree of expansion sufficient to prevent the therapeuticagent from flowing in the vessel beyond the expandable member. In theseembodiments, a blood flow protection member, such as a balloon, may bedisposed distal to (typically, downstream from) a drug delivery portionof the catheter. In other embodiments, a blood flow protection membermay be disposed proximal to (typically, upstream from) a drug deliveryportion of the catheter. In still other embodiments, two blood flowprotection members may be disposed proximate the drug delivery portionof the catheter, one member disposed distally, the other disposedproximally. In some embodiments of the method that make use of bloodflow prevention members in order to contain released drug into aconfined vascular space, the method may further include removing suchtrapped drug from the body after the ultrasonic treatment, and beforecollapsing the blood flow prevention members, allowing free flow ofblood through the treated portion of the vessel. In yet anotherembodiment, therapeutic agent may be delivered to the vessel wall inconjunction with delivering ultrasound energy or separately afterexposing the treatment area to ultrasound energy.

With regard to the formulation that includes the therapeutic agent thatis being delivered by embodiments of the method, such formulation istypically in the form of a liquid, either aqueous, organic, or acombination thereof, such as an emulsion. Formulations may furtherinclude dispersions of powders or particles, microbubbles, microspheres,nanospheres, liposomes, or any combination thereof. The emittedultrasound energy, per embodiments of the method, is sufficient toconvert the formulation including the therapeutic agent into droplets,microdroplets, or aerosols. The therapeutic agent within its formulationmay be dispersed from a drug delivery portion of the catheter at aconstant or a variable rate, or any combination thereof.

Embodiments of the method and devices provided herein may furtherinclude holding the formulation with the therapeutic agent in areservoir associated with the ultrasound/drug delivery catheter prior tothe delivery step. These embodiments may include delivering thetherapeutic agent formulation through one or more outlet ports incommunication with the reservoir. In some embodiments, the reservoir mayinclude a balloon, a stent or a mesh upon which the therapeutic agent iscoated, and from which the agent is released or eluted.

Some embodiments of the method and devices provided herein furtherinclude delivering an irrigation fluid from the ultrasound catheterwhile emitting ultrasound energy. In some of these embodiments, theirrigation fluid and the therapeutic agent formulation are deliveredtogether in a common mixture; in other embodiments, the irrigation fluidand the formulation including the therapeutic agent are delivered asseparate fluids. When delivered separately, the irrigation fluid and thetherapeutic agent formulation may be delivered from separate respectiveoutlet ports.

Some embodiments of the method and devices further include performing anangioplasty procedure before, during or after delivery of thetherapeutic agent and ultrasound energy, as summarized above. Theangioplasty or venoplasty procedure may be of any conventional type,such as balloon device, stent placement, atherectomy, laser angioplastyor venoplasty, ultrasound angioplasty or venoplasty, cryoplasty, or anycombination of such procedures. In some embodiments of this method,performing the angioplasty or venoplasty procedure may include advancinga balloon device over a guidewire to the target site, wherein thecombined ultrasound/drug delivery catheter is advanced over the sameguidewire.

Thus, one aspect of the invention includes an antistenotic treatment ata target site in a blood vessel that includes positioning a distal endof a combined ultrasound/drug delivery catheter to the site, deliveringa fluid formulation including a therapeutic agent to the site from theultrasound/drug delivery catheter, and emitting ultrasound energy fromthe ultrasound catheter while delivering the therapeutic agent, andperforming an angioplasty or venoplasty procedure at the target site.

Another aspect of the invention includes an antistenotic treatment at atarget site in a blood vessel that includes positioning a distal end ofa combined ultrasound/drug delivery catheter to the site, emittingultrasound energy from the ultrasound catheter without delivering thetherapeutic agent, and then delivering a therapeutic agent to the sitefrom the ultrasound/drug delivery catheter after first deliveringultrasound energy to the vessel wall.

In another aspect, the invention provides a method and devices fortreating stenosis or inhibiting restenosis which includes emittingultrasound energy from an ultrasound energy source and delivering atherapeutic agent intravenously into the human body.

In still another aspect, the invention provides a method and devices fortreating stenosis or inhibiting restenosis which includes emittingultrasound energy from an ultrasound energy source and delivering atherapeutic agent together with a contrast agent (either 100% or dilutedwith a conventional saline NaCl solution) into the artery or vein to thetreatment location.

In still another aspect, the invention provides a method and devices fortreating stenosis or inhibiting restenosis which includes emittingultrasound energy from an ultrasound energy source and delivering atherapeutic agent in solution with Carbamide (an organic compound withthe chemical formula (NH₂)₂CO) into the artery or vein to the treatmentlocation.

In yet another aspect, the invention provides a method and devices fortreating stenosis or inhibiting restenosis which includes emittingultrasound energy from an ultrasound energy source and delivering atherapeutic agent with Drug Eluting Stents, Bioabsorbable Stents, DrugEluting Balloons, Drug Eluting Stents, Porous Balloons, orMulti-Balloons to a treatment location that may include, but is notlimited to, the artery, vein or heart valve. Multi-balloon drug deliveryis also known as Weeping Balloons drug delivery, and includes aninflatable inner balloon enclosed by an expandable outer balloon thathas holes. The annular space between the inner balloon and the outerballoon is configured to promote delivery of the fluid evenly throughholes in the outer balloon to avoid problems of underloading and/oroverloading. The inner balloon may have various configurations includingbeing tapered relative to the outer balloon. The outer balloon may alsobe tapered accordingly.

The scope of the embodiments and methods described herein include theapplication of any therapeutic agent to a target site for a period oftime that is considered to be medically beneficial to the patient beingtreated. Any therapeutic drug may be exposed to the vessel for about onesecond to one hour to assure a maximum benefit of the delivered drug.

Suitable therapeutic agent(s) maybe delivered to the treatment area invariety of different forms and mixtures, either with or withoutultrasound, and with or without interventional procedure.

Some embodiments of the method and devices of antistenotic treatment mayfurther include removal of the therapeutic drug outside of the body, toavoid adverse systemic effects that may be caused by the therapeuticdrug.

All these methods and devices for treating stenosis or inhibitingrestenosis in an artery or vein by enhancing permeability of the vesselwall using ultrasound energy and delivering a therapeutic agent into theartery or vein may be achieved with endovascular or transcutaneoustechniques of delivery ultrasound energy. The therapeutic drug may bedelivered to the treatment site before, during and after ultrasoundenergy delivery.

Vascular permeability, often in the form of capillary permeability ormicrovascular permeability, characterizes the capacity of a blood vesselwall to allow for the flow of small molecules or even whole cells in andout of the vessel. Blood vessel walls are lined by a single layer ofendothelial cells. The gaps between endothelial cells (cell junctions)are strictly regulated depending on the type and physiological state ofthe tissue. The mechanical effect of ultrasound can disrupt this barrierby causing transcytosis, fenestration, channel formation, and/or openingof tight junction, thereby providing a free passage across the vascularwall to enhance delivery of therapeutic drugs.

Some other embodiments of the present invention include devices capableto further improve vessel permeability utilizing ultrasound energypropagated along a flexible member in the form of longitudinal waves,surface (radial or elliptic) waves and shear (transverse) waves, amongother waves, simultaneously.

Other embodiments of the present invention include devices and methodsutilizing ultrasound energy propagated in the form of longitudinalwaves, surface (radial or elliptic) waves and shear (transverse) waves(among other waves) to change compliance of plaque or vesselobstruction, and to increase vessel permeability.

Resistant fibrotic plaque or calcified plaque is a major limitation intreating arterial disease. Calcium deposits are frequent in patientswith advanced age, diabetes, renal insufficiency, hypertension, and ahistory of smoking. Calcified lesions are challenging to treat withtraditional endovascular therapy such as conventional angioplasty.Frequently, to displace the calcified plaque, balloon inflationpressures of more than 20 atm is required. Even after calcific plaque isdisposed, and the vessel is open, it still continues to be a significantbarrier for the delivery of therapeutic drug to the vessel wall tofurther reduce stenosis and inhibit restenosis. Ultrasound energy canerode and fracture calcified plaque while causing minimal injury to ahealthy tissue. Application of ultrasound longitudinal waves, surface(radial or elliptic) waves and shear (transverse) waves may inducemicro-cracks in the plaque and create micro-channels to furtherfacilitate therapeutic drug penetration and permeability of the vessel.

In another embodiment, the invention provides devices and methods forablating plaque, crossing Chronic Total Occlusions (CTO), as well asdissolving and removing blood clots and thrombus. This embodiment mayinclude advancing a distal end of an ultrasound delivery device into thevessel, vein or other locations where plaque or blood clots are located,activating the ultrasound catheter to emit radial ultrasound energy, andapplying aspiration or gravitational approach to further dissolve andremove blood clots outside the patient body. Use of therapeutic drugand/or microbubbles may enhance plaque and blood clots dissolving andremoval process.

In patients undergoing endovascular procedures involving a vascularobstruction removal or administration of therapeutic drugs, use ofultrasound energy may be beneficial in the delivery of liquid medicamentto further facilitate the distribution, delivery, absorption and/orefficacy of the medicament to improve clinical outcomes. Variousultrasonic catheter devices have been developed for use in ablating orotherwise removing obstructive material from blood vessels. For example,ultrasound devices with flexible ultrasound members for tissue ablation(either with or without therapeutic drugs) have been discussed in theprior art. Known devices enable translation of vibrations from thetransducer to the flexible probe causing the probe to oscillatelongitudinally or transversely. Longitudinal vibratory movement of thedistal head or probe causes disintegration and ablation of the adjacentlesion while simultaneously delivering therapeutic drugs. Examples ofsuch devices include U.S. Pat. Nos. 6,689,086 and 6,929,632 (both byNita, et al). Other examples of devices utilizing longitudinalvibrations are described in U.S. Pat. Nos. 6,855,123; 6,942,677;7,137,963; 7,297,131; 7,393,338; 7,621,929; 7,955,293, 8,133,236 and USPublication No. 2008/0108937 (all by Nita, et al.). Unlike longitudinalvibrations, transverse vibration emits a transverse ultrasonic energyalong the length of the probe body so that a plurality of transversenodes and anti-nodes are formed along the length of the probe. Examplesof such devices include U.S. Pat. Nos. 6,524,251; 6,551,337; 6,652,547;6,660,013; 6,695,781; 6,733,451; 6,866,670; 7,494,468; and 7,503,896(all by Rabiner, et al.). While the longitudinal waves oscillate in thelongitudinal direction or the direction of wave propagation, transversewaves oscillate perpendicular to the direction of propagation.Transverse waves are relatively weak compared to longitudinal waves andare known to not effectively propagate through liquids. Also, transversevibrations are known to produce unwanted stress along the ultrasoundtransmission member, often causing breakage of the ultrasoundtransmission member. While longitudinal waves (as described in the priorart) are powerful, their ability to deliver ultrasound energy to thesurrounding vessel wall is limited to the vibrating tip area. Therefore,longitudinal and transverse vibrations are limited in inducing uniformcellular changes along the treated vessel wall to further facilitatedrug therapies.

The present invention provides methods and devices configured to deliverultrasound surface waves or radial vibrational energy along anultrasound transmission member to the surrounding tissue, to eithersmall or large vessels or other cavities, and consequently increasingvessel drug uptake. Such devices provide a desired level of ultrasoundenergy to induce cellular changes while preventing vascular damage andreducing the potential of breakage for the ultrasound transmissionmember.

The present invention also provides methods and devices configured todeliver ultrasound energy and ultrasound enhanced delivery of Paclitaxelfor heart valve therapies. There are four valves in the heart: theaortic valve, pulmonary valve, mitral valve, and tricuspid valve; eachat the exit of one of the heart's four chambers. Heart valvestenosis/restenosis is a common valve disease. Balloon valvuloplasty isused primarily to treat heart valves when narrowing is present andmedical treatment has not corrected or relieved the related problems.During a balloon valvuloplasty, a specially designed balloon catheter isinserted into a blood vessel in the groin and guided to the heart. Thetip of the catheter is directed inside the narrowed valve, and theballoon is inflated and deflated several times to widen the valveopening. Once the valve has been widened enough, the balloon catheter isremoved.

Calcification of heart valves, also known as calcific degeneration,occurs when calcium builds up on a heart valve. This makes the leafletsof the valve harder and thicker and causes them to work lessefficiently. If the calcium build-up on a valve is severe enough, thevalve will no longer function properly, causing the valve to leak. Allfour valves of the heart can become calcified, but the aortic valve isthe most common site of calcification. While valvular angioplasty oftenoffers relief and cures the problem, calcification of heart valvesrequires surgery to remove calcium from leaflets to correct the opening(surgical valvotomy). Frequently, a valve replacement is necessary.Valvuloplasty and valvotomy play a very important role in valvedeployment. Therefore, a need for less invasive methods to treatvalvular stenosis/restenosis and calcifications still exists.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an embodiment of an ultrasound-enhanced drug deliverysystem.

FIGS. 2A, 2B, and 2C show various views of embodiments of ultrasoundcatheters for delivering a therapeutic agent to inhibit stenosis.

FIG. 2A shows a side view of an ultrasound-enhanced drug deliverycatheter.

FIG. 2B shows a view of a longitudinal cross section of an embodiment ofan ultrasound-enhanced drug delivery catheter.

FIG. 2C shows a view of a longitudinal cross section of an alternativeembodiment of an ultrasound-enhanced drug delivery catheter.

FIGS. 3A, 3B, and 3C show side views of embodiments of anultrasound-enhanced drug delivery catheter at a stenosis therapy site.

FIG. 3A shows an embodiment of the ultrasound catheter with holes at thedistal tip of the catheter for the delivery of a therapeutic agent.

FIG. 3B shows an embodiment of an ultrasound catheter with ports in thewall of the catheter body for the delivery of a therapeutic agent.

FIG. 3C shows an embodiment of an ultrasound catheter with therapeuticagent delivery sites in the form of holes at the distal tip of thecatheter and delivery ports in the wall of the catheter body.

FIG. 4A shows an embodiment of an ultrasound-enhanced drug deliverycatheter positioned for a balloon angioplasty or venoplasty procedureprior to ultrasound-enhanced drug delivery to a stenotic site.

FIG. 4B shows an embodiment of the ultrasound-enhanced drug deliverycatheter delivering therapeutic agent to a stenotic site following aballoon angioplasty or venoplasty procedure.

FIG. 5 shows an embodiment of an ultrasound-enhanced drug deliverycatheter delivering therapeutic agent to a stenotic site, the catheterfurther associated with an expanded distal protection balloon devicepositioned at the distal end of a guidewire, the expanded balloonfilling the vessel lumen and preventing downstream the flow oftherapeutic agent.

FIG. 6 shows an embodiment of an ultrasound-enhanced drug deliverycatheter with and an additional sheath for delivering a therapeuticagent to a vessel to inhibit restenosis.

FIG. 7A shows an embodiment of an ultrasound-enhanced drug deliverycatheter emitting ultrasound energy to the vessel wall first.

FIG. 7B shows an embodiment of an ultrasound-enhanced drug deliverycatheter delivery therapeutic agent after delivering ultrasound energy.

FIG. 8A shows a general view of an ultrasound-enhanced drug deliveryusing an external ultrasound source and a transcutaneous method todeliver ultrasound energy to the treatment area.

FIG. 8B shows an embodiment of an ultrasound-enhanced drug deliveryusing external ultrasound source and a transcutaneous method to deliverultrasound energy to the treatment area, and further showingendovascular catheter to deliver a therapeutic agent.

FIG. 9 shows an ultrasound device having a flexible distal member todeliver ultrasound energy to the treatment area to improve vessel drugpermeability.

FIG. 10 shows an ultrasound device with a distal ultrasound transmissionmember according to another embodiment of the present invention.

FIG. 11 is a partial cross-sectional view of the proximal portion of theultrasound device shown in FIG. 10.

FIGS. 12-15 show different embodiments of the distal ultrasoundtransmission member shown in FIG. 10.

FIG. 16A illustrates a side view of an ultrasound catheter positionedwithin a heart valve.

FIG. 16B illustrates a side view of single-balloon valvuloplasty usingan ultrasound catheter according to another embodiment of the presentinvention.

FIG. 16C illustrates a side view of a therapeutic drug deliveryaccording to another embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present application provides new methods and devices to improve thetreatment of vascular stenosis and re-stenosis using ultrasoundtechnology to enhance delivery of therapeutic agents directly to atargeted therapeutic site, such as a stenotic site on an artery or veinwall. These methods may be understood as forms of anti-stenosistreatment, which may include treatment of a stenotic site to modifyplaque compliance and to increase the patency of the afflicted vessel,or it may also include treatment of a site previously treated orcontemporaneously treated to inhibit or prevent restenosis. Aspects ofthe invention, including devices and the types of therapeutic agentswhose efficacy may be enhanced by the provided technology will bedescribed first in general terms, and then, further below, will bedescribed in the context of FIGS. 1-16.

The methods described herein employ endovascular sonophoresis and inducevasodilatation, a process that creates micro-indentations in a vesselwall during ultrasound energy delivery; these indentations increasevessel wall permeability and permit a higher level of therapeutic agentdelivery to the target cell interior. When ultrasound energy isdelivered at a frequency range of 1 kHz-10 MHz and at power below 20watts to the vessel wall, the sound waves transiently disrupt theintegrity of the plaque and the cell membranes without creatingpermanent damage to the vessel wall or surrounding tissue. In a typicalembodiment of the invention, for example, ultrasound energy from asource in contact or in proximity to a vessel wall, at a frequency ofabout 20 kHz and a power of less than about 10 watts is used to inducesonoporation and vasodilatation by creating micro-cracks andmicro-channels in the plaque, and to modify the integrity of cellmembranes. Power levels above 20 watts may cause permanent damage to thevessel wall such as thermal damage, necrosis and vessel rupture whenultrasound energy is delivered by an endovascular catheter. Power levelsabove 20 watts may also cause skin burns or wounds when ultrasoundenergy is delivered transcutaneously through the skin.

As used herein, “power” of the endovascular catheter deliveringultrasound energy refers to watts of power delivered by the distal endor tip of the catheter per mm² of the tip's or distal end'scross-sectional area. For transcutaneous delivery of ultrasound energy,“power” refers to a total amount of watts of power of the ultrasounddevice per cm² of the contact area between the device and the skin.

Sonoporation uses the interaction of ultrasound energy with the presenceof locally or systemically delivered drugs to temporarily permeabilizethe cell membrane allowing for the uptake of DNA, drugs, and othertherapeutic compounds from the extracellular environment. This membranealteration is transient, leaving the compound trapped inside the cellafter ultrasound exposure. Sonoporation combines the capability ofenhancing gene and drug transfer with the possibility of restrictingthis effect to the desired area and the desired time. Thus, sonoporationis a promising drug delivery and gene therapy technique, limited only bya full understanding regarding the biophysical mechanism that results inthe cell membrane permeability change.

Oscillation of delivered therapeutic agents is considered to be aprimary mechanism causing sonoporation. However, inertial cavitation,microstreaming, shear stresses, and liquid jets as a result of linearand nonlinear oscillations all may be causal mechanisms contributing tosonoporation as well. Propagating ultrasound pressure waves have animpact in regulating endothelial cell function, cell morphology,metabolism, and gene expression. Fluid shear stress caused bypropagating ultrasound waves induces a rapid, large, and sustainedincrease in Nitric Oxide activity. In the very acute setting (seconds)of shear stress, calcium-activated potassium channels open and increaseNitric Oxide production. Nitric Oxide contributes to vessel dilation byinhibiting vascular smooth muscle constriction. This Nitric Oxidedelivery may improve targeted therapeutic delivery into vasculartissues.

In some embodiments of the invention, the method and devices may includeconverting a therapeutic agent from liquid form into spray viaultrasound, a method known as nebulization that converts the lowviscosity drug into an ultra fine spray as it exits from the cathetertip. Thus, this allows a rapid cellular uptake of drug and enables it toeasily pass through the hydrophobic barrier of cell membranes. As thedrug is delivered through the catheter, it is mechanically pulverizedinto droplets from the vibrating distal end of the catheter, furtherincreasing permeation of the drug into the vessel wall.

In one aspect, methods and improved devices are provided for inhibitingstenosis, restenosis, and/or hyperplasia concurrently with and/or afterintravascular intervention. As used herein, the term “inhibiting” meansany one of reducing, treating, minimizing, containing, preventing,curbing, eliminating, holding back, or restraining. In some embodiments,ultrasound enhanced delivery of therapeutic agents to a vessel wall withincreased efficiency and/or efficacy is used to inhibit stenosis orrestenosis. Such a method may also minimize drug washout and provideminimal to no hindrance to endothelialization of the vessel wall.

As used herein. “treatment site” refers to an area in a blood vessel orelsewhere in the body that has been or is to be treated by methods ordevices of the present invention. Although “treatment site” will oftenbe used to refer to an area of a vessel wall that has stenosis orrestenosis (“a stenotic site”), the treatment site is not limited tovascular tissue or to a site of stenosis. The term “intravascularintervention” includes a variety of corrective procedures that may beperformed to at least partially resolve a stenotic, restenotic, orthrombotic condition in a blood vessel, usually an artery or vein of ahuman body. Commonly, at least in current practice, the therapeuticprocedure may also include balloon angioplasty or venoplasty. Thecorrective procedure may also include directional atherectomy,rotational atherectomy, laser angioplasty or venoplasty, stenting, orthe like, where the lumen of the treated blood vessel is enlarged to atleast partially alleviate a stenotic condition which existed prior tothe treatment. The treatment site may include tissues associated withendovascular locations, or outside of endovascular location, includingbodily lumens, organs, ducts or localized tumors. In one embodiment, thepresent devices and methods reduce the formation or progression ofrestenosis and/or hyperplasia that may follow an intravascularintervention. A “lumen” may be any blood vessel in the patient'svasculature, including veins, arteries, aorta, heart valves andparticularly including coronary and peripheral arteries, as well aspreviously implanted grafts, shunts, fistulas and the like. Inalternative embodiments, methods and devices described herein may alsobe applied to other body lumens, such as the biliary duct, which aresubject to excessive neoplastic cell growth. Examples of internalcorporeal tissue and organ applications include various organs, head,nerves, glands, ducts, and the like.

As used herein. “therapeutic agent” includes any molecular species,and/or biologic agent that is either therapeutic as it is introduced tothe subject under treatment, becomes therapeutic after being introducedto the subject under treatment, for example by way of reaction with anative or non-native substance or condition, or any other introducedsubstance. Examples of native conditions include pH (e.g., acidity),chemicals, temperature, salinity, osmolality, and conductivity; withnon-native conditions including those such as magnetic fields,electromagnetic fields (such as radiofrequency and microwave), andultrasound. In the present application, the chemical name of any of thetherapeutic agents is used to refer to the compound itself and topro-drugs (precursor substances that are converted into an active formof the compound in the body), and/or pharmaceutical derivatives,analogues, or metabolites thereof (bio-active compound to which thecompound converts within the body directly or upon introduction of otheragents or conditions (e.g., enzymatic, chemical, energy), or environment(e.g., pH).

The scope of the invention includes the use of any therapeutic agentwhose medicinal effectiveness may be enhanced by the use of ultrasonicenergy, as described herein. For the purposes of illustration, a numberof therapeutic agent classes will be identified in order to convey anunderstanding the invention. These classes of agents and the specificlisted agents are not intended to limit the scope or practice of theinvention in any way; the scope of the invention includes anytherapeutic agent that may be considered beneficial in the treatment ofa patient. Further, these agents may be delivered by any appropriatemodality, as for example, by intra-arterial direct injection,intravenously, orally, or a combination thereof.

In some embodiments, examples of therapeutic agents may includeimmuno-suppressants, anti-inflammatories, anti-proliferatives,anti-migratory agents, anti-fibrotic agents, proapoptotics,vasodilators, calcium channel blockers, anti-neoplastics, anti-canceragents, antibodies, anti-thrombotic agents, anti-platelet agents,IIb/IIIa agents, antiviral agents, mTOR (mammalian target of rapamycin)inhibitors, non-immunosuppressant agents, and combinations thereof.

Specific examples of therapeutic agents that may be used in variousembodiments include, but are not limited to: mycophenolic acid,mycophenolic acid derivatives (e.g., 2-methoxymethyl derivative and2-methyl derivative), VX-148, VX-944, mycophenolate mofetil, mizoribine,methylprednisolone, dexamethasone, CERTICAN™ (e.g., everolimus, RAD),rapamycin. ABT-773 (Abbot Labs). ABT-797 (Abbot Labs). TRIPTOLIDE™,METHOTREXATE™, phenylalkylamines (e.g., verapamil), benzothiazepines(e.g., diltiazem), 1,4-dihydropyridines (e.g., benidipine, nifedipine,nicarrdipine, isradipine, felodipine, amlodipine, nilvadipine,nisoldipine, manidipine, nitrendipine, barnidipine (HYPOCA™)).ASCOMYCIN™. WORTMANNIN™. LY294002. CAMPTOTHECIN™, flavopiridol,isoquinoline. HA-1077 (1-(5-isoquinolinesulfonyl)-homopiperazinehydrochloride). TAS-301 (3-bis(4-methoxyphenyl)methylene-2-indolinone).TOPOTECAN™, hydroxyurea, TACROLIMUS™ (FK 506), cyclophosphamide,cyclosporine, daclizumab, azathioprine, prednisone, diferuloymethane,diferuloylmethane, diferulylmethane, GEMCITABINE™, cilostazol (PLETAL™),tranilast, enalapril, quercetin, suramin, estradiol, cycloheximide,tiazofurin, zafurin, AP23573, rapamycin derivatives,non-immunosuppressive analogues of rapamycin (e.g., rapalog, AP21967,derivatives' of rapalog), CCI-779 (an analogue of rapamycin availablefrom Wyeth), sodium mycophernolic acid, benidipine hydrochloride,sirolimus, rapamine, metabolites, derivatives, and/or combinationsthereof.

In some embodiments, the method and devices may include introducinganti-cancer therapeutic agents for promoting intracellular activation byirradiating the vessel wall cells with ultrasound to cause passage ofthe these drug into the vessel wall to inhibit stenosis and restenosis.In some embodiments, for example, an anti-angiogenesis agent may be usedto inhibit stenosis or restenosis.

Ultrasound enhancement provided by the apparatus and method and devicesof the present invention may be of particular benefit when thetherapeutic agent being administered is highly toxic. Specific examplesof such drugs are the anthracycline antibiotics such as adriamycin anddaunorubricin. The beneficial effects of these drugs relate to theirnucleotide base intercalation and cell membrane lipid bindingactivities. This class of drugs has dose limiting toxicities due toundesirable effects, such as bone marrow suppression, andcardiotoxicity.

Drugs within the scope of the present invention also include: AdriamycinPFS Injection (Pharmacia & Upjohn); Adriamycin RDF for Injection(Pharmacia & Upjohn); Alkeran for Injection (Glaxo WellcomeOncology/HIV); Aredia for Injection (Novartis); BiCNU (Bristol-MyersSquibb Oncology/Immunology); Blenoxane (Bristol-Myers SquibbOncology/Immunology); Camptosar Injection (Pharmacia & Upjohn);Celestone Soluspan Suspension (Schering); Cerubidine for Injection(Bedford); Cosmegen for Injection (Merck); Cytoxan for Injection(Bristol-Myers Squibb Oncology/Immunology); DaunoXome (NeXstar);Depo-Provera Sterile Aqueous Suspension (Pharmacia & Upjohn); DidronelI.V. Infusion (MGI); Doxil Injection (Sequus); Doxorubicin Hydrochloridefor Injection, USP (Astra); Doxorubicin Hydrochloride Injection, USP(ASTRA); DTIC-Dome (Bayer); Elspar (Merck); Epogen for Injection(Amgen); Ethyol for Injection (Alza); Etopophos for Injection(Bristol-Myers Squibb Oncology/Immunology); Etoposide Injection (Astra);Fludara for Injection (Berlex); Fluorouracil Injection (RocheLaboratories); Gemzar for Injection (Lilly); Hycamtin for Injection(SmithKline Beecham); Idamycin for Injection (Pharmacia & Upjohn); Ifexfor Injection (Bristol-Myers Squibb Oncology/Immunology); Intron A forInjection (Schering); Kytril Injection (SmithKline Beecham); LeucovorinCalcium for Injection (Immunex); Leucovorin Calcium for Injection,Wellcovorin Brand (Glaxo Welcome Oncology/HIV); Leukine (Immunex);Leustatin Injection (Ortho Biotech); Lupron Injection (Tap); MesnexInjection (Bristol-Myers Squibb Oncology/Immunology); MethotrexateSodium Tablets, Injection, for Injection and LPF Injection (Immunex);Mithracin for Intravenous Use (Bayer); Mustargen for Injection(Bristol-Myers Squibb Oncology/Immunology); Mutamycin for Injection(Bristol-Myers Squibb Oncology/-Immunology); Navelbine Injection (GlaxoWellcome Oncology/HIV); Neupogen for Injection (Amgen); Nipent forInjection (SuperGen); Novantrone for Injection (Immunex); Oncaspar(Rhone-Poulenc Rorer); Oncovin Solution Vials & Hyporets (Lilly);Paraplatin for Injection (Bristol-Myers Squibb Oncology/Immunology);Photofrin for Injection (Sanofi); Platinol for Injection (Bristol-MyersSquibb Oncology/Immunology); Platinol-AQ Injection (Bristol-Myers SquibbOncology/Immunology); Procrit for Injection (Ortho Biotech); Proleukinfor Injection (Chiron Therapeutics); Roferon-A Injection (RocheLaboratories); Rubex for Injection (Bristol-Myers SquibbOncology/Immunology); Sandostatin Injection (Novartis); Sterile FUDR(Roche Laboratories); Paclitaxel-Taxol Injection (Bristol-Myers SquibbOncology/Immunology); Taxol Abraxane-ABI-007 (Abraxis Bioscience);Taxotere for Injection Concentrate (Rhone-Poulenc Rorer); TheraCys BCGLive (Intravesical) (Pasteur Merieux Connaught); Thioplex for Injection(Immunex); Tice BCG Vaccine, USP (Organon); Velban Vials (Lilly); Vumonfor Injection (Bristol-Myers Squibb Oncology/Immunology); Zinecard forInjection (Pharmacia & Upjohn); Zofran Injection (Glaxo WellcomeOncology/HIV); Zofran Injection Premixed (Glaxo Wellcome Oncology/HIV);Zoladex (Zeneca).

Other classes of drugs within the scope of the present invention includealkylating agents which target DNA and are cytoxic, nutagenic, andcarcinogenic. All alkylating agents produce alkylation through theformation of intermediate. Alkylating agents impair cell function bytransferring alkyl groups to amino, cartoryl, sulfhydryl, or phosphategroups of biologically important molecules. Such drugs include Busulfan(Myleran), Chlorambucil (Leukeran), Cyclophosphamide (Cytoxan, Neosor,Endoxus), Ifosfamide (Isophosphamide, Ifex), Melphhalan (Alkeran,Phenylalanine Mustargen, L-Pam, L-Sarcolysin), Nitrogen Mustargen(Mechlorethamine, Mustargen, HIV.sub.2), Nitrosonceas (Carmustine CBCNV,Bischlorethyl, Nitrosourea), Lomustine (CCNV, Cyclohexyl ChlorethylNitrosouren, CeeNV), semustine (methyl-CCNV) and Streptozocin(Strephozotocin), Streptozocin (Streptozoticin, Zanosan), Thiotepa(Theo-TEPA, and Triethylenethrophosphoranide).

Agents with alkylator activity include a group of compounds that includeheavy metal alkylators (platinum complexes) that act predominantly bycovalent bonding and “non-classic alkylating agents” are also within thescope of the present invention. Such agents typically contain achloromethyl groups and an important N-methyl group. Such other agentsinclude Amsacrine (m-AMSA, msa, Acridinylanisidiale,4′-)(9-acridinylamins) methanesulfin-m-anesidide, Carboplatin(Paraplatin, Carboplatinum, CBDCA), Cisplatin (Cesplatinum), Dacabazine(DTIC, DIC dimethyltricizenormidazoleconboxamide), Hexamethylmelanine(HMM, Altretanine, Hexalin) and Procarbazine (Matulane, Natulanan).

Antimetabolite drugs are also included within the scope of the presentinvention, such as Azacitidine (5-azacylidine, ladakamycin) Cladribine(2-CdA, CdA, 2-chloro-2-deoxyadenosine) Cytarabine (CytosineArabinoside, Cytosar, Tarabine), Fludarabine (2-fluoroadeninearabinoside-5-phosphate, fludara), Fluorouracil (5-FV, Adrucil, Efuctex)Hydroxyurea (hydroxycarbamide, Hydrea), Leucovorin (Leucovorin Calcium),Mercaptopurine (G-MP, Purinethol), Methotrexate (Amethopterin),Mitoguazone (Methyl-GAG), Pentostatin (2′-deorycoformycin) andThioguanine (6-TG, aminopurine-6-thiol-hemihydrate).

Antitumor antibiotics commonly interfere with DNA through intercalation,whereby the drug inserts itself between DNA base pairs. Introduction ofultrasound enhances this interference. Such drugs include Actinomycin DCCosmegen, Dactinomycin), Bleomycin (Blenoxane) Daunoxubibin(rubidomycin). Doxorubicin (Adriamycin, Hydroxydaunorubicin,hydroxydaunomycin, Rubex), Idarubicin (44-demethylorydan norubicin,Idamycin), Mithramycin (Mithracin, Plicamycin), Milomycin C andMitorantione (Novantrone).

Plant alkaloids bind to microtubular proteins thus inhibitingmicrotubule assembly; and ultrasound may enhance such binding. Suchalkaloids include Etoposide, Paclitaxel (Taxol), Treniposide,Vinblastine (Velban, Velsar, Alkaban), Vincristine (Oncovin, Vincasar,Leurocristine) and Vindesine (Eldisine).

Hormonal agents include steroids and related agonists and antagonists,such as adrenocorticosteroids, adrenocorticosteroid inhibitors,mitolane, androzens, antiandiozens, antiestrogens, estrogens, LHRHagonists, progesterones.

Antiangiogenesis agents include Fumagillin-derivative TNP-470, PlateletFactor 4, Interleukin-12, Metalloproteinase inhibitor Batimastat,Carboryaminatriarzole, Thalidomide, Interferon Alfa-2a, Linomide andSulfated Polysaccharide Tecogalan (DS-4152).

The drugs that may be useful in preventing in-stent restenosis fall intofour major categories: anti-neoplastics, immunosupressives, migrationinhibitors, and enhanced healing factors.

Anti-proliferative compounds include Paclitaxel, QP-2, actinomycin,statins and many others. Paclitaxel was originally used to inhibit tumorgrowth by assembling microtubules that prevent cells from dividing. Ithas also recently been observed to attenuate neointimal growth.

Immunosupressives are generally used to prevent the immune rejection ofallogenic organ transplants. The general mechanism of action of most ofthese drugs is to stop cell cycle progression by inhibiting DNAsynthesis. Everolimus, Sirolimus, Tacrolimus (FK-506), ABT-578,interferon, dexamethasone, and cyclosporine all fall into this category.The Sirolimus derived compounds appear especially promising in theirability to reduce intimal thickening.

Migration inhibitors are aimed at preventing endothelial cell migrationto the inside of the stent. Once smooth muscle cells migrate to theluminal side of the stent, they can produce extracellular matrix andbegin to occlude blood flow. Therefore, inhibiting their migration canhave great therapeutic applications for preventing in-stent restenosis.Examples of these compounds are batimastat and halofuginone. Batimastat,for example, is a potent inhibitor of matrix metalloproteinase enzymes.It can prevent the matrix degradation that is necessary for cells tofree themselves to move. If the cells cannot move, they cannot invadethe stent area.

Enhanced Healing Factors: Vascular endothelial growth factor (VEGF)promotes healing of the vasculature. In the context of stents, thiswould heal the implantation site and reduce platelet sequestration dueto injury related chemotaxis. Nitrous oxide donor compounds may alsoreplicate this effect. Healing of the vessel wall seems to be thegentlest approach to preventing ISR, but healing factors are still inthe early stages of development for this application.

Sirolimus (rampamycin) and Paclitaxel are the two drugs that arecommonly used in drug eluting stents. Sirolimus is a macrocyclic lactoneimmunosuppressive agent that inhibits the cell division cycle andcellular proliferation by promoting kinase activation and halting thecellular growth phase. Paclitaxel also inhibits the cell cycle, butworks via a different mechanism than Sirolimus. Paclitaxel binds tomicrotubules in dividing cells and causes them to assemble, therebypreventing mitosis. Paclitaxel is in the anti-neoplastic family ofcompounds. Together, Paclitaxel and Sirolimus are two of the mostpromising drugs for use in stents, as several others have run intoproblems with lumen loss, late thrombosis, delayed restenosis, andaneurysm formation.

For the removal of blood clots and thrombus, examples of therapeuticagents may include (i) tissue plasminogen activator, tPA. BB-10153,rTPA, Urokinease, Streptokinase, Alteplase and Desmoteplase, (ii)antiplatelet agents such as aspirin. Clopidorgel and Ticclopidine, and(iii) Glib/IIIa inhibitors, such as Abciximab. Tirofiban andEptifibatide.

The devices of the present invention may be configured to release ormake available the therapeutic agent at one or more treatment phases,the one or more phases having similar or different performance (e.g.,delivery) profiles. The therapeutic agent may be made available to thetissue at amounts which may be sustainable, intermittent, or continuous;in one or more phases and/or rates of delivery; effective to reduce anyone or more of smooth muscle cell proliferation, inflammation, immuneresponse, hypertension, or those complementing the activation of thesame. Any one of the at least one therapeutic agents may perform one ormore functions, including preventing or reducingproliferative/restenotic activity, reducing or inhibiting thrombusformation, reducing or inhibiting platelet activation, reducing orpreventing vasospasm, or the like.

The total amount of therapeutic agent made available to the tissuedepends in part on the level and amount of desired therapeutic result.The therapeutic agent may be made available at one or more phases, eachphase having similar or different release rate and duration as the otherphases. The release rate may be pre-defined. In an embodiment, the rateof release may provide a sustainable level of therapeutic agent to thetreatment site. In another embodiment, the rate of release issubstantially constant. The rate may decrease and/or increase asdesired.

These therapeutic agents may be provided and or delivered to the body inany conventional therapeutic form or formulation, such as, merely by wayof example: liquid, powder, particle, microbubbles, microspheres,nanospheres, liposomes and/or combinations thereof.

Some embodiments of the invention may also include delivering at leastone therapeutic agent and/or optional compound within the bodyconcurrently with or subsequent to an interventional treatment. Morespecifically, the therapeutic agent may be delivered to a targeted sitethat includes the treatment site concurrently with or subsequent to theinterventional treatment. By way of example:

-   -   a. A therapeutic agent may be delivered to the treatment site as        a stand-alone therapy in treatment of native stenosis or        restenosis, without any other contemporaneous remedy or        treatment such as provided by a physical or mechanical dilation.    -   b. A therapeutic agent may be delivered to the treatment site as        the only therapy in treatment of stenosis or restenosis in        grafts.    -   c. A therapeutic agent may be delivered to the treatment site        following any suitable interventional procedure.    -   d. A therapeutic agent may be delivered to the treatment site        before an interventional procedure, during, after an        interventional procedure, or combinations thereof.    -   e. A therapeutic agent may be delivered to the treatment site        concurrently with a blood flow, with a partial blood flow or        with no blood flow using blood flow protection devices.

The therapeutic agent may be made available to the treatment site atamounts which may be sustainable, intermittent, or continuous; at one ormore phases; and/or rates of delivery.

In one aspect of the invention, improved ultrasound delivery cathetersare provided that incorporate means for infusing liquid medicaments(e.g., drugs or therapeutic agents) concurrently or in conjunction withthe delivery of ultrasonic energy. The delivery of the ultrasonic energythrough the catheter concurrently with the infusion of therapeuticagents aids in rapidly dispersing, disseminating, distributing, oratomizing the medicament. Infusion of at least some types of liquidmedicaments concurrently with the delivery of ultrasonic energy mayresult in improved or enhanced activity of the medicament due to: a)improved absorption or passage of the medicament into the target tissueor matter and/or b) enhanced effectiveness of the medicament upon thetarget tissue due to the concomitant action of the ultrasonic energy onthe target tissue or matter.

Delivery of a therapeutic agent may face a different release rate duringinitial catheter activation compared to a normal and desirable release.Usually, the initial release of the therapeutic agent is at a higherrate/level than preferred due necessity to flesh the catheter beforeactivation. To avoid the therapeutic agent downstream losses, distal orproximal protection or both may be used. Distal and/or proximalprotection devices are known in the art, as, for example, a simple,low-pressure balloon catheter: when the balloon is expanded, it stopsblood flow. In such cases when distal and/or proximal protection devicesare used to prevent downstream flow of the therapeutic agent, a residualportion of the therapeutic agent may be removed or retrieved outside thebody using conventional vacuum methods after exposure to the vessel wallfor about one second to one hour.

Another object of the present invention is to provide an ultrasoundapparatus to deliver ultrasound energy to the target tissue thatutilizes at least three principal modes: longitudinal waves, shear(transverse) waves and surface (radial or elliptic) waves, among othersincluding Lamb waves. Love waves, Stoneley waves or Sezawa waves. Inlongitudinal waves, the oscillation occurs in the longitudinal directionor the direction of wave propagation. In shear waves, oscillation occurstransverse to the direction of propagation. Transverse waves arerelatively weak compare to longitudinal waves and are known to noteffectively propagate through liquids. Surface waves are mechanicalwaves that propagate along the interface between differing media.Surface waves travel the surface of a solid material or liquidpenetrating to a depth of one wavelength. Surface waves combine both alongitudinal and transverse motion to create an elliptic orbit motion.The major axis of the ellipse is perpendicular to the direction of thepropagation of the wave.

Methods and devices of the invention that have been described above ingeneral terms will now be described in further detail in the context ofFIGS. 1-16. Referring to FIGS. 1 and 2, one embodiment of an ultrasoundfor delivering ultrasound and therapeutic agents for treating and/orinhibiting stenosis and/or restenosis is shown. The ultrasound system 90includes an ultrasonic catheter device 100, which has an elongatecatheter body 101, having an inside lumen/space 111. The catheter 100comprises a proximal end 102 and a distal end 103, and an ultrasoundtransmission member/wire 110 disposed in the lumen 111 (FIGS. 2B and2C).

The ultrasound transmission member or wire 110 is attached to the tip104 on the distal end of the catheter 100 and to a connectorassembly/knob 105 at the proximal end of the catheter 100. Theultrasound catheter 100 is operatively coupled, by way of a sonicconnector 112 (FIG. 2A) located within the proximal connectorassembly/knob 105, to an ultrasound transducer 120. The ultrasoundtransducer 120 is connected to a signal generator 140. The ultrasoundtransducer 120 may be provided inside the generator 140 (not shown). Thesignal generator 140 may be provided with a foot actuated on-off switch141.

When the on-off switch 141 is turned on, the signal generator 140 sendsan electrical signal via line 142 to the ultrasound transducer 120,which converts the electrical signal to vibrational energy. Suchvibrational energy subsequently passes through the sonic connector 120(inside the connector assembly/knob 105) to the catheter device 100, andis delivered via the ultrasound transmission member 110 (FIGS. 2B and2C) to the distal tip 104. A guidewire 150 may be used in conjunctionwith the catheter device 100 having the entry at the distal tip 104 andexit port 151.

The generator 140 includes a device operable to generate variouselectrical signal wave forms such as continuous, pulse or combinationsof both within frequencies range between 1 kHz and 10 MHz, and producespower of up to 20 watts at the distal end of the catheter tip 104. Thus,ultrasound energy may be provided in continuous mode, pulse mode, or anycombination thereof. Also, to minimize stress on the ultrasoundtransmission member 110 during activation, the operational frequency ofthe current and/or the voltage produced by the ultrasound generator 140may be modulated. Movement of the distal end of the drug deliverycatheter may be provided in several forms vibrational energy such aslongitudinal fashion, transverse fashion, radial (surface waves) fashionor a combination of all three forms. Propagation of vibrational energyfrom the vibrational energy source through the ultrasound catheter maybe provided in the similar way. An injection pump 160 or IV bag (notshown) maybe connected by way of an infusion tube 161 to an infusionport or sidearm 109 of the Y-connector 108. The injection pump 160 isused to infuse coolant fluid (e.g., 0.9% NaCl solution) from theirrigation fluid container 162 into the inner lumen 111 of the catheter100. Such flow of coolant fluid serves to prevent overheating of thecatheter 100 during vibrational energy delivery. Due to the desirabilityof infusing coolant fluid into the catheter body 101, at least one fluidoutflow channel 107 is located either in the distal tip 104 or in thecatheter body 101 at the distal end 103 to permit the coolant fluid toflow out of the distal end of the catheter 100. Such flow of the coolantfluid through the catheter body 100 serves to bathe the outer surface ofthe ultrasound transmission member. The temperature and/or flow rate ofcoolant fluid may be adjusted to provide adequate cooling and/or othertemperature control of the ultrasound transmission member. Such anirrigation procedure may also be performed by conventional syringes andother devices suitable for liquid injection.

In addition to the foregoing, the injection pump 160 may be activated bythe foot actuated on-off switch 141 at the same time as the generator140. Therapeutic agents may be delivered together with an irrigationfluid into the catheter device 100 using the injection pump 160 andcarried to the distal end 103 of the catheter 100. Therapeutic agentsmay be mixed, dissolved, synthesized or emulsified with other drugssolvents, liquids, or irrigation fluid and delivered to human body usinginjection pump 160. The injection pump 160 may also be implementedinside the generator 140 (not shown). When injected into the irrigationlumen, such therapeutic agents combined with irrigation liquid flowthrough the catheter inner lumen 111 and cool the ultrasoundtransmission member 110 of the ultrasound catheter 100 while activated.When a therapeutic agent leaves the ultrasound catheter 100 at distalend 103, it will contact and at least partially be absorbed by the bloodvessel wall. Optionally, therapeutic agent may be infused separatelyinto the catheter 100 through the other port 180 of the Y-connector 108,thus, delivering a therapeutic agent independently through a separatelumen (not shown) or not as a mixture with irrigation fluid. Atherapeutic agent can be delivered into the catheter 100 through theport 180 using syringe 181 or other injection device concurrently withirrigation fluid. Optionally, a therapeutic agent may be delivered tothe distal end 103 of the catheter 100 independently of the catheter100. For example, in one embodiment, a separate lumen for a therapeuticagent inside the catheter body 101 may be provided (not shown).Alternatively, an additional sheath 602 around the catheter 100 as shownin FIG. 6 may be employed. In another alternative embodiment, a directinjection of a therapeutic drug from a guiding catheter or introducersheath into the treatment area may be utilized.

Although the ultrasound catheter 100 in FIG. 1 is illustrated as a“monorail” catheter device, in alternative embodiments the catheter 100may be provided as an “over-the-wire” or guidewire-free device, as arewell known in the art.

Referring now to FIGS. 2A. 2B, and 2C, more detailed views ofembodiments of the ultrasound catheter 100. In this embodiment, theultrasound catheter 100 includes an elongated flexible catheter body 101having an elongated ultrasound transmission member 110 that extendslongitudinally through the inner lumen of the catheter body 111. A sonicconnector 112 is positioned on the proximal end of the catheter 100 andattached to the ultrasound transmission member 110. The sonic connector112 provides the attachment of the ultrasound catheter, morespecifically the ultrasound transmission wire to an external ultrasoundenergy source. The sonic connector 112 is housed inside the knob 105 andis attached to the ultrasound transducer 120 when performing aprocedure. While the knob 105 serves as a secondary interface betweenthe ultrasound catheter 100 and the ultrasound transducer 120, the sonicconnector 112 is securely attached to the transducer horn and transfersultrasound vibrations from the transducer 120 to the ultrasoundtransmission member 110. The ultrasound transmission member 110 carriesvibrational energy to the tip 104 located at the distal end of thecatheter 100.

In an embodiment wherein the ultrasound catheter 100 is constructed tooperate with a guidewire, an inner guidewire tube 113 may be extendedwithin the inner lumen 111 of the catheter body 101 and attached to thetip 104 on the distal end. The other end of the guidewire tube 113 maybe attached along the length of the catheter body 101. The guidewireexit port 151 may be positioned closer to the end of the catheter bodyor closer to the proximal end of the catheter body 100. The catheter 100shown may be deployed with the use of the guidewire as either a“monorail” or an over-the-wire arrangement.

The catheter body 101 maybe formed of any suitable material, includingflexible polymeric material such as nylon (Pebax™) as manufactured byAtochimie (Cour be Voie. Hauts Ve-Sine. France). The flexible catheterbody 101 is generally in the form of an elongate tube having one or morelumens extending longitudinally therethrough.

The distal tip 104 is a substantially rigid member firmly affixed to thetransmission member 110 and optionally affixed to the catheter body 101.The distal tip 104 has a generally rounded configuration and may beformed of any suitable rigid metal or plastic material, preferablyradio-dense material so as to be easily discernible by radiographicmeans.

The tip 104 is attached to the ultrasound transmission member 110 bywelding, adhesive, soldering, crimping, or by any other appropriatemeans. A firm affixation of the ultrasound transmission member 110 tothe distal tip 104 and sonic connector 112 is required for vibrationalenergy transmission from the transducer 120 to the tip 104. As a result,the distal tip 104, and the distal end 103 of the catheter body 101 iscaused to undergo vibrations.

The ultrasound transmission member 110 may be formed of any materialcapable of effectively transmitting the ultrasonic energy, such as, byway of example, metal, fiber optics, polymers, and/or compositesthereof. In some embodiments, a portion or the entirety of theultrasound transmission member 110 may be formed of one or more shapememory or super elastic alloys. Examples of super-elastic metal alloysthat are appropriate to form the ultrasound transmission member 30 ofthe present invention are described in detail in U.S. Pat. No. 4,665,906(Jervis), U.S. Pat. No. 4,565,589 (Harrison). U.S. Pat. No. 4,505,767(Quin), and U.S. Pat. No. 4,337,090 (Harrison). The disclosures of U.S.Pat. Nos. 4,665,906; 4,565,589, 4,505,767; and 4,337,090 are expresslyincorporated herein by reference as they describe the compositions,properties, chemistries, and behavior of specific metal alloys which aresuper-elastic within the temperature range at which the ultrasoundtransmission member 110 of the present invention operates, any and allof which super-elastic metal alloys may be usable to form thesuper-elastic ultrasound transmission member 110.

A therapeutic agent is infused through the inlet port 109 of theY-connector 105 and the lumen 111 of the catheter body 101 whendelivered as mixture with an irrigation fluid (FIG. 1). If a therapeuticagent is infused separately, the port 180 may be used. The outlets portsfor the therapeutic agent from the catheter 100 either when drug isdelivered as a mixture with the irrigation fluid or separately throughthe port 180 are located at the distal end 103 of the catheter 100. Insome embodiments, outlet ports 106 are located in the distal tip 104only, and are positioned to deliver a therapeutic agent (and irrigationfluid) in a radial manner, around the distal tip. In another embodiment,outlet ports 107 maybe located in the wall of the catheter body 101 atits distal portion 103.

Various other arrangements and positioning of the respectivedrug/irrigation outlet ports 106 and 107 may be utilized in otherembodiments of the invention. The size and number of these outlet portsmay vary depending on the specific intended function of the catheter100, the volume or viscosity of the therapeutic drug intended to beinfused, and/or the relative size of the therapeutic area to which thedrug is to be applied. In other embodiments, outlet ports may be locatedin both mentioned locations as shown in FIG. 2C. In some embodiments,outlet ports are located in such order that irrigation liquid andtherapeutic drug are distributed evenly around the distal end 103, andin such fashion that the same volume and pressure at each outlet portare achieved to assure uniform distribution and application of atherapeutic drug to the vessel wall.

With reference now to FIGS. 3A, 3B, and 3C, in some embodiments of theinvention, a therapeutic agent may be delivered to a vascular stenosissite as a stand-alone treatment (i.e., without contemporaneousangioplasty, venoplasty or stenting). Such a separate therapeutic agenttherapy may be used, for example, when the vascular stenosis has notclosed a vessel by more than 50% and there is no significant blood flowdisturbance effect in supplying blood to surrounding areas and organs.Alternatively, to improve the final result, in some embodiments aconventional angioplasty or venoplasty procedure such as balloonangioplasty or venoplasty, stent, atherectomy, laser treatment orcombinations of these therapies may be used before or after atherapeutic agent delivery procedure.

In FIG. 3A, the distal end 103 of the ultrasound catheter 100 isintroduced inside the vessel 300 over the guidewire 150 and positionedwithin the stenosis or treatment area 301. The distal tip 104 of theultrasound catheter 100 has a series of radial holes 106 that serve asoutlet ports for irrigation fluid and therapeutic drug. When ultrasoundenergy is delivered to the catheter 100, the distal tip 104 vibratescausing the irrigation fluid and therapeutic drug passing out of thecatheter 100 to mix together, to be pulverized into droplets 302, and todisperse outward, all of these effects increasing permeation of the druginto the vessel wall. Also, the vibrating tip 104 of the ultrasoundcatheter 100 may cause local vasodilatation or sonophoresis around thesurrounding tissue, thereby creating micro indentation in the treatmentarea 301 due to cavitation, increasing its permeability, and allowingthe applied drug to penetrate better into the vessel wall. Delivery ofultrasound energy from the tip 104 to the treatment area 302 promotesintracellular activation of cells by irradiating tissue with ultrasoundenergy to cause an improved passage of a therapeutic drug into thetreatment area 301.

To cover a larger area of treatment, the catheter tip 104 may berepositioned within the vessel 300, either longitudinally, radially, orby both orientations as required. The catheter 100 may also be rotatedwithin the vessel 300 if desired. The embodiment of FIG. 3B differs fromthat of FIG. 3A in that therapeutic agent outlet ports 107 are locatedin the wall of the catheter body 101 instead of at the tip 104 as shownin FIG. 3A. The embodiment in FIG. 3C shows the provision of both typesof outlet ports 106, 107 as illustrated in FIG. 3A and FIG. 3B combined.During ultrasound energy delivery, outflow mixture of the irrigationfluid and therapeutic drug from ports 106 and 107 is being dispersed,pulverized into droplets 302 and delivered to the treatment site 301.

Alternative embodiments of devices and methods of the invention (notshown) include applying or coating the therapeutic agent to the exteriorof a balloon that is attached to the distal end of the ultrasoundcatheter. Inflation of the balloon enables approximation of thetherapeutic drug to the vessel wall and at least partial stasis of theblood flow through the blood vessel. In combination with ballooninflation, ultrasound energy at the catheter tip is activated which maycause local vasodilatation or sonophoresis around the surrounding tissueto enable greater penetration of the drug delivery. Also, ultrasoundenergy in combination with the fluid elements on the inside lining ofthe blood vessel may enable transformation of the drug coating from theballoon to the blood vessel.

Other alternative embodiments of devices and methods for the presentinvention (not shown) include the use of a porous balloon attached tothe end of the ultrasound catheter. In these embodiments, the balloon isinflated with the therapeutic agent inside, and the balloon weeps thetherapeutic drug as the pressure inside the balloon increases. While thedrug weeps through the balloon materials or through small holes in theballoon, ultrasound energy is activated to enable local vasodilatationor sonophoresis around the surrounding tissue to aid in increased drugpenetration into the targeted blood vessel.

Still other alternatives embodiments of devices and methods theinvention (not shown) include ultrasound-assisted delivery oftherapeutic agents that are delivered either, before, during or afterthe endovascular recanalization step, to improve arterial stenosis orrestenosis. Types of stenosis that could be treated by this technologyand method include minor atherosclerotic disease to chronic totalocclusions (CTO). Recanalization of the vessel can be achieved by amultitude of ablation technologies (e.g. ultrasound, atherectomy,radiofrequency) or mechanical means (e.g., balloon). In one specificexample, the same ultrasound device may be used both to ablate the CTOand to assist delivery of the therapeutic agent to the vessel wall whilerecanalizing the CTO site. Also, as another alternative, after theinitial recanalization and delivery of therapeutic agent to the targettissue, a follow up therapy such as balloon angioplasty, venoplasty,stent or other may be employed.

Yet further alternative embodiments of devices and methods the invention(not shown) include the use of a mesh device that is made of metal,polymer, or a combination of such materials that is attached to the endof the ultrasound catheter. Such mesh devices may be used in a similarway as the balloon devices described above, either coated or not coatedwith a therapeutic agent.

In most cases, ultrasound enhanced drug delivery to treat stenosis andrestenosis may be applied to existing atherosclerotic disease. However,it may also be used in some embodiments as a preventive measure in areasthat are vulnerable to atherosclerotic disease or stenosis generally,such as an area referred to as a “vulnerable plaque”.

Referring now to FIGS. 4A and 4B, one embodiment of the method of theinvention may include first performing a conventional angioplasty orvenoplasty (FIG. 4A) and then delivering a therapeutic agent (FIG. 4B).In this embodiment, as shown in FIG. 4A, a balloon catheter 400 having aballoon 401 is introduced over the wire 150 inside the vessel 400 to thetreatment area 402. FIG. 4B shows a previously diseased area 402compressed by the balloon 401 inflation. The ultrasound catheter 100 isintroduced over the same guidewire 150 to a newly reconfigured diseasearea 410 (post balloon angioplasty or venoplasty). A therapeutic agentis delivered to the distal end of the ultrasound catheter 100 havingoutlet ports 106 located in the tip 104, and outlet port 107 located inthe wall of the catheter body 101. The mode of operation and action isthe same as that described in FIGS. 3A, 3B, and 3C.

In other embodiments of the invention, as shown in FIG. 5, a stenosistreatment system 500 may include an ultrasound/drug delivery catheter520 coupled with a distal flow protection device 501 to preventdownstream flow of blood and therapeutic drug. In this embodiment, alow-pressure compliant balloon 502 is mounted on the distal end of theprotection device 501, in this case a small, guidewire size device. Onecurrent example of such device is the PercuSurge Guardwire®(Medtronic/PercuSurge. Minneapolis. Minn.). The balloon 502 is inflatedaccordingly and the ultrasound energy enhanced drug delivery isperformed as described in FIGS. 3A-3C. The balloon 502 of the protectiondevice 501 may be fully inflated as shown in FIG. 5, so that notherapeutic drug is delivered beyond the treatment site 510. If desired,the balloon 502 may be deflated and inflated to allow ultrasoundenhanced drug delivery to a whole length of the treatment area 510. Suchblood flow protection feature may be achieved also by installing asimilar balloon onboard the ultrasound catheter 100, proximal totherapeutic agent outlets. An example of such a device is described byPassafaro et al. (U.S. Pat. No. 5,324,255). A balloon feature describedby Passafaro et al., onboard the ultrasound device may serve twofunctions, as an angioplasty or venoplasty device and as a blood flowprotection device, as desired. Also, blood flow protection at thetreatment area may be achieved using a proximal protection device suchas guiding catheter with a balloon onboard. These devices are known inthe art and will not be described further.

An alternative embodiment (not shown) to prevent downstream flow ofblood and therapeutic drug is inflating a balloon or a mesh deviceproximal to the ultrasound drug delivery location. Such a balloon ormesh device can be integrated with the ultrasound/drug delivery or be aseparate catheter device. Use of a balloon or mesh elements in any ofthe embodiments described in this application can be used to preventdownstream delivery of the drug and to enable faster delivery, or thedelivery of greater amounts, of drug to the targeted tissue.

An alternative embodiment (not shown) to prevent downstream flow ofblood and therapeutic drug migration when a flow protection device isused may include retrieving residual mixture of drug/blood/solventoutside the body to minimize any systemic toxic effect.

FIG. 6 shows another embodiment of the present invention. The ultrasoundcatheter 100 is delivered to the diseased area 601 inside the vessel 600over the wire 150. An additional single lumen sheath 602 is positionedover the ultrasound catheter 100. A therapeutic agent is delivered froman independent source and separately from the irrigation system of thecatheter 100. The additional sheath 602 is a single lumen catheterhaving an inner lumen 603 extending longitudinally, and is positionedover the ultrasound catheter 100. A therapeutic agent is deliveredthrough the lumen 603 and exits the sheath 602 at the distal end 604thereof which is positioned in the vicinity of the distal end 103 of theultrasound catheter 100. Activation of the ultrasound catheter 100causes the catheter distal tip and the immediate area of the catheter100 distal portion 103 to vibrate. Vibrations of the distal end 103causes a therapeutic drug delivered from the distal end of the sheath602 to be pulverized into droplets 302 and delivered to the treatmentsite 601. Also, a vibrating tip 104 of the ultrasound catheter 100 maycontinue to induce local vasodilatation around the surrounding tissue602, further increasing its permeability, so that the applied drugpenetrates into the vessel wall. Due to the nature of therapeutic drugsupply from the sheath 602, a flow protection may be appropriate.

Any of the therapeutic agents detailed above may be introduced to atreatment site using the methods and devices described herein, with orwithout coolant fluid (e.g., 0.9% NaCl solution). Alternatively oradditionally, in other embodiments, a therapeutic agent may be deliveredalong with a contrast agent, such as an angiographic contrast agent, fordiagnostic purposes. Any suitable contrast agent may be used incombination with a therapeutic agent of the present invention, deliveredtogether or separately, either with contrast agent diluted with the 0.9%NaCl solution or at 100% concentration. Also, a therapeutic agent may bedelivered in solution with Carbamide [(NH₂)₂CO] into the artery or veinto the treatment location.

An illustrative clinical example of an application of the invention willnow be provided, in which the described ultrasound enhanced delivery oftherapeutic agent is applied to the treatment of a patient with astenotic coronary artery or vein. Following the diagnosis of a chestpain or angina in the patient, it is radiographically determined thatthe left coronary artery or vein is significantly occluded and thatblood flow to the left side of hart is impaired. A coronary guidecatheter is inserted percutaneously into the patient's femoral artery orvein and such guide catheter is advanced and engaged in the leftcoronary ostium. A guide wire is advanced through the lumen of the guidecatheter to a location where the distal end of the guidewire is advancedirectly through or immediately adjacent to the obstruction within theleft coronary artery. An ultrasound catheter 100, an embodiment of thepresent invention, as shown in FIGS. 1-6, is advanced over thepre-positioned guide wire 150 by inserting the exteriorized proximal endof the guide wire into the guide wire passage formed in the distal tip104 of the catheter 100. The catheter 100 is advanced over the guidewire 150, such that the proximal end of the guide wire 150 emerges outof guide wire exit port 151. The ultrasound catheter 100 is advanced tothe coronary obstruction to be treated as shown in FIGS. 3A-3C.Thereafter, a container 162 of sterile 0.9% NaCl solution may beconnected, by way of a standard solution administration tube 161 to thecoolant infusion side arm 109 and a slow flow of saline solution ispumped or otherwise infused through sidearm 109, through the lumen 111of the catheter body 101 and out of outlet ports located at the tip 104or the distal portion 107 of the catheter body 101, as shown in FIG. 3B.An intravenous infusion pump 160 is then used to provide such flow ofcoolant fluid through the catheter. The proximal connector assembly 105of the catheter 100 is then connected to the ultrasound transducer 120via sonic connector 112, and the ultrasound transducer 120 iscorrespondingly connected to the signal generator 140 so that, whendesired, ultrasonic energy may be passed through the catheter 100. Atherapeutic agent is mixed with a sterile 0.9% NaCl coolant solution anddelivered from the bottle 162 and tube 161 to the coolant infusion port109 of the catheter 100. Alternatively, a therapeutic agent may beinjected through the other port 180 and syringe 181, separately from thecoolant fluid.

To initiate delivery of a therapeutic agent, the flow of coolantinfusion mixed with a therapeutic agent is delivered from the bottle 162to the infusion port 109 and maintained at an appropriate flow ratewhile the signal generator 140 is activated by compression of on/offfoot pedal 141. When actuated, electrical signals from the signalgenerator 140 pass through cable 142 to ultrasound transducer 120.Ultrasound transducer 120 converts the electrical signals intoultrasonic vibrational energy and the ultrasonic energy is passedthrough the ultrasound transmission member of the catheter 100 to thedistal tip 104 and its distal portion 103. The distal portion 103 of thecatheter 100 may be moved, repositioned back and forth by the operatorto deliver therapeutic agent to the entire treatment site therebytreating the stenosis of the occluded left coronary artery. After theultrasonic enhanced delivery of a therapeutic agent has been completed,and after the desired dose of drug has been delivered through thecatheter 100 to the treatment site 301, the infusion of irrigation fluidand therapeutic agent is ceased and the signal generator 140de-actuated. Thereafter, the ultrasound catheter 100 and guidewire 150are extracted from the coronary artery, into the guide catheter andoutside the body, and then, the guide catheter is retracted and removedfrom the body. The ultrasound enhanced delivery of a therapeutic agentis considered as the first line therapy

Referring now to FIGS. 7A and 7B, another method according to thepresent invention may include first performing a conventionalangioplasty or venoplasty, which is represented by a reconfigureddiseased area 701 (post balloon angioplasty or venoplasty), thendelivering only a therapeutic ultrasound energy using the ultrasoundcatheter 100 as shown in FIG. 7A. The ultrasound catheter 100 is capableof delivering therapeutic agent, but in this embodiment emits onlyultrasound energy to the vessel wall around diseased area 701 in theform of sonic waves 702. Ultrasound energy application may be providedby any other suitable ultrasound catheter. The ultrasound catheter 100can be repositioned within the vessel back and forth over the guidewire150 as shown by the double arrow 703 to cover a whole area of treatmentand to create desirable sonoporation and vasodilatation effects for abetter drug permeability into the vessel wall. After delivery ofultrasound energy, the ultrasound catheter is removed and a conventionaldrug delivery catheter 710 as shown in FIG. 7B is introduced over theguidewire 150 to a newly treated area after the initial ultrasoundexposure to the area 701. A therapeutic agent is delivered from anindependent source, such as through drug outlets 715 at the distal endof a drug delivery catheter 710. The drug delivery outlets 715 arepositioned in the vicinity of the newly modified treatment area 720, andthe therapeutic agent 716 is delivered to the vessel wall. The drugdelivery catheter maybe reposition back and forth in the vessel as shownby the double arrow 704 represent the entire treatment area 720, anduntil the application of the therapeutic agent is completed. Due to thenature of certain therapeutic drugs, a flow protection may beappropriate (not shown) for such drugs.

Also, all above described embodiments related to the application of atherapeutic agent to the vessel wall may be carried out in conjunctionwith emitting ultrasound energy to the vessel wall from an externalultrasound device in a transcutaneous fashion as shown in FIGS. 8A and8B. FIG. 8A shows a human lower extremity (e.g., leg) 805 with anexternal ultrasound transducer 806 positioned on the skin 807 around thetreatment area. The external ultrasound energy source can be atransducer 806 connected via a cable 808 to an ultrasound generator 809.The ultrasound generator 809 converts line power into a high frequencycurrent that is delivered to the transducer 806. The transducer 806comprises piezoelectric crystals that convert high frequency currentinto ultrasonic energy that is delivered into the leg 805 through theskin 807. The generator 809 includes a device operable to generatevarious electrical signal wave forms such as continuous, pulse orcombinations of both, within a frequency range between 1 kHz and 10 MHz,and can produce a power output of up to 100 watts at transducer 806. Theultrasound energy may be provided in continuous mode, pulse mode, or anycombination thereof. Also, to improve efficacy and minimize stress aswell as reduce a potential thermal damage to the skin 807 between thetransducer 806 and the surrounding skin area during ultrasound energyactivation, the operational frequency, as well as current/voltageproduced by the ultrasound generator 809, as well as timing/pulsing maybe modulated. In addition, ultrasound transmission gel 811 (e.g., suchas that manufactured by Graham-Field. Bay Shore, New York) may be usedbetween the transducer 806 and the skin 807 to reduce skin burns. Anon-limiting example of a suitable ultrasound device includes the TIMI3Transcutaneous System (Santa Clara. Calif.). As shown in FIG. 8B, thetransducer 806 produces ultrasound waves 802 that propagate through theskin 807 and leg tissue 803 to the treatment area 801 of the vessel 800.The treatment area 801 may often be a reconfigured diseased area afterinitial angioplasty or venoplasty. The drug delivery catheter 810 ispositioned over the guidewire 150 inside the vessel 800 around thetreatment area 801. A therapeutic agent 816 is delivered through thedistal outlet ports 815 of the drug delivery catheter 810 in a radialfashion towards the treatment area 801. The therapeutic agent 816 can bedelivered before, during and after ultrasound energy delivery from thetransducer 806. The vibrating transducer 806 produces sound waves 802that penetrate through the leg skin 807 and the tissue 803 to thetreatment area 801, and induces local vasodilatation and sonoporationwithin the surrounding tissue, further increasing its permeability, sothat the applied drug penetrates into the vessel wall. Radial waves mayalso impact surrounding vessels that are away from the vibrationalenergy source since such waves tend to penetrate and propagate up to onewavelengths distance from vibrational source. Consequently, othervessels in the area where such vibrational energy is applied may alsodemonstrate increased permeability. When therapeutic drugs are appliedto such non-diseased areas (either intended or not intended), it mayalso show angiogenesis.

FIG. 9 illustrates another method to deliver ultrasound energy to thetreatment area to enhance vessel permeability according to the presentinvention. An ultrasound catheter 902 has a distal ultrasound flexiblemember or probe 903 with a distal rounded, non-traumatic tip 904.Ultrasound energy produced by the generator 140 and the transducer 120as shown in FIG. 1 is delivered through the ultrasound transmissionmember 110 as shown in FIGS. 2B and 2C. The transmission member 110 hasa flexible distal member 903 that is located outside the ultrasoundcatheter 902. The ultrasound catheter 902 and distal flexible member 903are positioned within the treatment (diseased) area 901 inside thevessel 900. The entire length of the flexible member 903 is exposed tothe diseased (stenosis, plaque) area 901 inside the vessel 900. There isa distal marker 905 located on the end of the catheter 902 whichprovides positioning and visualization under fluoroscopy for thecatheter 902 and flexible member 903.

As used herein, three modes of propagated ultrasound energy(longitudinal waves 907, transverse waves 909 and surface waves 908) maybe delivered along the flexible member 903. While it is difficult toshow schematically all these three sound waves simultaneously, FIG. 9provides representative wave illustrations that serve for explanationpurpose only and which do not limit the claims made herein.

The entire length of the flexible member 903 serves as an active memberthat delivers ultrasound energy to the adjacent diseases area 901. Theinjection pump 160 is used to infuse coolant fluid (e.g., 0.9% NaClsolution) from the irrigation fluid container 162 (as shown in FIG. 1)into the inner lumen 906 of the catheter 902. Such flow ofcoolant/irrigation fluid serves to prevent overheating of the ultrasoundtransmission member 110 and flexible member 903 during ultrasound energydelivery. In addition, once the irrigation fluid leaves the inner lumen906 of the catheter 905, it works as a medium to propagate longitudinalwaves 907, surface waves 908 and transverse waves 909 toward theadjacent tissue 901. Other ultrasound waves are also propagated from theultrasound transmission member 110, but play a less important role inchanging plaque compliance and increasing vessel permeability.

The flexible member 903 can be made from any metal suitable to propagateultrasound energy, and preferably has a circular shape having a diameteranywhere between 0.1 mm to 5 mm and a length that can vary anywherebetween 0.1 mm and 500 mm. The operational frequency for the flexiblemember can be between 1 Hz-10 MHz. Despite the fact that ultrasoundenergy is commonly defined as vibrations that occur at a frequency abovethe audible range (17-20 kHz), a more suitable term for frequency belowand above this range is vibrational energy.

While the time of ultrasound energy exposure depends on vessel size andthe severity of the disease, the exposure time within the treated areacan be anywhere between 1 second to 60 minutes. Ultrasound powerdelivered to the vessel wall should not exceed 20 Watts to avoid tissuedamage.

The method described in FIG. 9 may also be used to treat stenosis,restenosis of heart valves either calcific or non-calcific. In suchapplication, a diseased area 901 may be located on the surface of theheart valve and surrounding tissue.

FIG. 10 illustrates another catheter device according to the presentinvention. The catheter device comprises an ultrasound transmissionmember 1000 having a distal tip 1001, a catheter body 1002 having aradiopaque marker 1003 and an attached guidewire lumen 1004 having aproximal exit port 1005. Connected to the proximal end of the catheterbody 1002 are a proximal connector 1006 having three ports 1007, 1008and 1009, and a proximal knob 1010 having a distal portion 1011 andproximal portion 1012. A guidewire 1013 is extended through theguidewire lumen 1004 and the guidewire exit port 1005. The guidewire1013 and guidewire lumen 1004 are shown for reference only as thepresent invention can be applied to both catheters that include and notinclude a guidewire. The catheter body 1002 can be formed of anypolymeric material. The flexible catheter body 1002 is preferably anelongate tube having one or more lumens extending longitudinally. Thedistal portion of the three arm connector 1006 is connected to theproximal end of the catheter body 1002 using techniques that arewell-known in the catheter art. Extending longitudinally through thelumen of the catheter body 1002 is the elongate ultrasound transmissionmember 1000. The proximal end 1100 of the ultrasound transmission memberis extended through the proximal end of the catheter body 1002, threearm connector 1006 and knob 1010 (as shown in FIG. 11), and the veryproximal end of the ultrasound transmission member 1100 is connected tothe sonic connector 1101 (see FIG. 11), which is removable connectableto the ultrasound transducer (not shown). With such an arrangement,ultrasound energy passes from the ultrasound transducer (not shown)through the sonic connector 1101, the proximal end of the ultrasoundtransmission member 1000, and is delivered to the distal tip 1001 of theultrasound transmission member 1000 as shown in FIG. 10. In oneembodiment, the ultrasound transmission member 1000 may be formed of anymaterial capable of effectively transmitting the ultrasonic energy, andis preferably made from metals including but not limited to titanium,aluminum and their alloys. Also, the ultrasound transmission member 1000can be formed with one or more materials which exhibit super-elasticity.Examples of super-elastic metal alloys which are usable to form theultrasound transmission member of the present invention are described indetail in U.S. Pat. No. 4,665,906 (Jervis); U.S. Pat. No. 4,565,589(Harrison); U.S. Pat. No. 4,505,767 (Quin); and U.S. Pat. No. 4,337,090(Harrison). The disclosures of U.S. Pat. Nos. 4,665,906; 4,565,589;4,505,767; and 4,337,090 are expressly incorporated herein by reference.

FIG. 11 illustrates the details of the proximal part of the catheterdevice shown in FIG. 10. The distal portion 1011 of the knob 1010 has apartially threaded bore 1106. The port 1009 of the three arm connector1006 also has external threads 1107 and is attached to the distal end1011 of the catheter knob 1010 by threadably engaging the threaded part1107 of the port 1009 inside the bore 1106. An injection pump, IV bag orsyringe (not shown) can be connected to an infusion port or sidearm 1007of the three arm connector 1006. The injection pump, IV bag or syringecan be used to infuse coolant fluid into and/or through the lumen(s) ofthe catheter body 1002. Such flow of coolant fluid may be utilized toprevent overheating of the ultrasound transmission member 1000. The port1008 of the three arm connector 1006 may serve to deliver therapeuticagents and to aspirate drugs after use if needed. It also can be used toevacuate ablated plaque and blood clots. The very proximal end of theultrasound transmission member 1000 is attached to a sonic connector1101 which is configured to couple the proximal end of the ultrasoundtransmission member 1000 to the horn of the ultrasound transducerlocated inside the transducer housing 120 as shown in FIG. 1. Theproximal portion 1012 of the knob 1010 has a bore 1102 that accommodatesthe sonic connector 1101. The sonic connector 1101 is attached to theproximal end of the ultrasound transmission wire 1000 at a joint 1109using conventional methods such as crimping welding, soldering orbonding. The sonic connector 1101 is positioned within the bore 1102with a pin 1103 placed through a hole 1104 in the proximal portion 1012of the knob 1010. The sonic connector 1101 has also a through-hole 1105which accommodates the pin 1103 and secures the sonic connector 1101inside the bore 1102 in a position aligned with the pin 1103. The sonicconnector 1101 has some freedom to move around the pin 1103, so it canfreely vibrate and propagate ultrasound energy to the ultrasoundtransmission member 1000.

The ultrasound catheter shown in FIG. 10 is configured to propagateultrasound energy along the proximal end 1100 and produce mostlylongitudinal and surface waves along the ultrasound transmission member1000, and to further propagate surface waves to the surrounding tissuedirectly or through irrigation medium. To achieve the most optimaledifice, an absorber in the form of a series of polymer o-rings 1108 orother means for mitigating transverse motions, such as elasticelement(s), can be positioned inside the proximal bore 1106 of the knob1011 and between the bottom of the bore 1106 and the distal end of thethreaded part 1107 of the port 1009. A preferable location forpositioning the o-rings 1108 is outside the ¼λ (one-quarter wavelength)distance from the sonic connector 1101 as shown in the FIG. 11. Such apositioning will reduce transverse motions while allowing longitudinalmotions to propagate through the ultrasound transmission member 1000.The number of o-rings 1108, or the length and size of other elasticelement(s), can be selected depending on the intensity requirement ofthe surface waves along the ultrasound transmission member 1000.

FIG. 12 shows an alternative structure of ultrasound transmission member1000. As described above, the distal ultrasound flexible member 1000 mayundergo some undesired transverse motions that may cause the ultrasoundtransmission member 1000 to break or experience failure. To reduce suchpotential problems and related clinical challenges, a polymer sheath1200 can be positioned along the ultrasound transmission member 1000.Such a polymer sheath 1200 will allow ultrasound energy in form oflongitudinal waves to propagate to the distal tip 1001 of the ultrasoundtransmission member 1000, while reducing transverse motions, therebygenerating surface waves along the ultrasound transmission member 1000and further propagating these surface waves to the treatment area. Inaddition, a polymer shell 1201 maybe added or fused around the distaltip 1001 for further tissue protection since a significant amount ofheat may be concentrated around this very distal area of the ultrasoundtransmission member 1000 during ultrasound energy delivery. Polymermaterials that can be used for both the polymer sheath 1200 and thepolymer shell 1201 may include but is not limited to: PTFE, PTE,polyurethane, polyamide, polyethylene or nylon. The polymer sheath 1200may also be further extended proximally into the catheter body 1002. Thecatheter body 1002 may be repositioned along the ultrasound transmissionmember 1000 as required by the length of the treated area. The catheterbody 1002 includes a guidewire lumen 1004 that may be extended beyondthe distal end of the catheter body 1002. The guidewire exit port 1005of the guidewire lumen 1004 may be positioned at, or exit at, anydesired location along the catheter body 1002, including at thethree-arm connector 1106 and the knob 1010. The polymer material usedfor the polymer shell 1201 and the polymer sheath 1200 can be mixed witha radiopaque metallic powder to provide a better visibility of theultrasound transmission member 1000 and the distal tip 1001 underfluoroscopy.

The ultrasound transmission member 1000 is configured to propagateultrasound energy in form of surface waves along the length of theultrasound transmission member 1000 that is exposed to the treatmentarea, and located between the distal tip 1001 and the distal end of thecatheter 1002. The ultrasound transmission member 1000 can have at leasttwo regions of a different (decreasing) cross-sectional dimension (notshown) to maintain a desired flexibility adjacent the distal end anddurability at the proximal end. The ultrasound transmission member 1000extends longitudinally through the catheter 1002 and is connected to thesonic connector 1101 as shown in FIG. 11. The ultrasound transmissionmember 1000 may be tapered or narrowed, or have an increasedcross-sectional dimension so as to generally decrease the rigidity ofthe ultrasound flexible member 1000 and to cause amplification of theultrasound energy transmitted to the distal portion of the ultrasoundtransmission member 1000. The ultrasound transmission member 1000 mayhave a plurality of intermediate tapered sections, progressively taperedsections or a combination of both, having diameters that progressivelydecrease from the area adjacent to the proximal region toward the distalregion. The ultrasound transmission member 1000 may also include acontinuous diameter or tapered structure, while the distal tip 1001 ofthe flexible member may be larger, smaller, or have the same dimensionas the intermediate dimension of the ultrasound transmission member1000. The proximal end 1100 of the ultrasound transmission member 1000as shown in FIG. 11 may include any dimensional configuration requiredto optimize ultrasound energy delivery to the ultrasound transmissionmember 1000.

FIG. 13 shows another alternative assembly of the ultrasoundtransmission member 1000. As previously mentioned, the ultrasoundtransmission member 1000 has a smaller cross sectional area along itslength than at the proximal end 1100. Also, the ultrasound transmissionmember 1000 may include several narrowed regions to amplify energypropagation. Such a structure is prone to stress concentration along theultrasound transmission member 1000 that may cause fracture or breakagethereof. Several measures may be taken to avoid such breakage, includingincreasing the size of the ultrasound transmission member 1000, andusing energy pulsing or modulation to mitigate stress concentration,among others. However, in case the ultrasound transmission member 1000breaks, parts of the ultrasound transmission member 1000 may be leftbehind in the patient's body even when the ultrasound transmissionmember is protected by the polymer sheath 1200 shown in FIG. 12. Toaddress such a possibility, an anchor member 1300 can be extended alongthe ultrasound transmission member 1000 and attached at an attachmentpoint 1301 to the distal end 1001 of the ultrasound transmission member1000. At the proximal end, the anchor member 1300 may be attached to theultrasound transmission member 1000, the catheter 1002, the connector1006, or the proximal knob 1010 shown in FIGS. 10 and 11, or to theproximal end 1100 shown in FIG. 11. The anchor member 1300 will ensurethat the ultrasound transmission member 1000 can be entirely removedfrom the patient's body in the case of breakage of the ultrasoundtransmission member 1000. The anchor member 1300 may be made of metal,polymer or combination of both. A radiopaque marker 1302 may be attachedat the distal end of the ultrasound transmission member 1000 if requiredto provide radiopacity at the distal tip 1001. Attachments of the anchormember 1300 and radiopaque marker 1302 can be done by conventionalmethods such as bonding, welding, soldering, and crimping, among other.The distal tip 1001 may be further covered with the polymer shell 1201on the distal-most end to encapsulate the radiopaque marker 1302, thedistal portion of the anchor member 1300, the attachment 1301, and thedistal tip 1001 itself. In addition, the polymer sheath 1200 may beextended along the ultrasound transmission member 1000 and the anchorwire 1300 to mitigate transverse vibrations of the ultrasoundtransmission member 1000. The construction of the catheter 1002 can besimilar to one shown in FIG. 12, and include the radiopaque marker 1003,and the guidewire lumen 1004 having a proximal exit port 1005.

FIG. 14 shows another alternative structure of the ultrasoundtransmission member 1000. An additional metallic tip 1400 can beattached to the distal end 1001. Such a metallic tip may be helpful forcrossing tight stenosis and recanalization of Chronic Total Occlusions(CTO) which often will have a well-organized and hardened compositionthat is otherwise impossible to cross with conventional guidewires. Thedevices in the embodiments described above may not always be suitablefor such applications because the plastic shell 1201 shown in FIGS. 12and 13 may be easily damaged while interfacing or crossing hard calcificplaque. A radiopaque marker 1302 is also attached to the ultrasoundtransmission member 1000. If the metallic tip 1400 is sufficientlyradiopaque, the radiopaque marker 1302 may not be necessary. Theradiopaque marker 1302 may also be attached directly to the metallic tip1400. An anchor member 1300 can also be attached to the tip 1001, andthe polymer sheath 1200 and polymer shell (if necessary) may be attachedin a similar fashion as shown in FIGS. 12 and 13. The anchor member 1300may also be attached to the metallic tip 1400 at the attachment point1301. The construction of the catheter 1002 can also be similar toconstructions shown in FIGS. 12 and 13, and can include the radiopaquemarker 1003, and the guidewire lumen 1004 having a proximal exit port1005.

FIG. 15 illustrates the ultrasound transmission member 1000 shown inFIG. 14, and in use with an additional catheter 1500 that is positionedaround the ultrasound transmission member 1000 and around the catheter1002. The additional catheter 1500 may serve an aspiration purpose asillustrated with arrows 1501, either to remove ablated tissue,therapeutic drug after use, blood clots or irrigation provided forcooling of the ultrasound transmission member 1000 during ultrasoundenergy delivery. The aspiration catheter 1500 may be positioned alongthe distal end of the catheter 1002 and the ultrasound transmissionmember 1000 as needed to safely and effectively apply ultrasound energyto the treated area while removing ablated tissue, therapeutic drugafter use, blood clots or irrigation material. A further alternative maybe to provide a single catheter with two lumens that can perform thesame functions as the catheter 1002 and the aspiration catheter 1500(not shown). The aspiration catheter 1500 can be made of a polymer tube,metal tube or combinations of both. The use of aspiration and ultrasoundenergy producing surface waves at the same time may be particularlybeneficial for removing blood clots or thrombus from the patient's body.Examples of blood clots removal includes locations within theendovascular system and outside of the endovascular system, but are notlimited to Arterial and Venous Thrombolysis. Ischemic and HemorrhagicStroke. Deep Vein Thrombolysis (DVT). Pulmonary Embolism and any othercavities in human body where blood clots needs to be removed includingorgans and the head. Removing tissue, blood clots or liquids may beachieved by various configurations/locations of the ultrasoundtransmission member 1000 and the catheter 1002 in respect to theaspiration catheter 1500. The ultrasound transmission member 1000 may beexposed outside of the catheter 1002 at a length that is clinicallynecessary, and such range may be between 0.1 mm and 500 mm. Duringblood-clot removal or other tissue removal, the ultrasound transmissionmember 1000 and/or the catheter 1002 may be positioned outside of theaspiration catheter 1500 as shown in FIG. 15. Also, in anotherembodiment, the ultrasound transmission member 1000 and the catheter1002 may be positioned fully inside the aspiration catheter 1500 (notshown). In such case, aspiration pressure will suck or extract bloodclots or other tissue inside the catheter 1500 as shown by arrows 1501.Once blood clots or other removed tissue reach entry into the catheter1500, it is macerated and dissolved by ultrasound energy generated fromthe ultrasound transmission member 1000 to facilitate continuous tissueremoval. In such case, the ultrasound in the form of longitudinal andsurface waves liquefies blood clots and removed tissue to furtherprevent the catheter 1500 from clogging and obstruction. Aspiration maybe provided by vacuum pump(s) that are separate from the system shown onthe FIG. 1, or such a vacuum pump(s) may be incorporated in thegenerator 160.

Devices shown in FIGS. 10-15 may also be used to treat heart valvestenosis and restenosis including calcifications. Calcification of heartvalves often preclude effective valvuloplasty, and in such caseultrasound devices can be used to change compliance of the calcifiedportion of the treated heart valve by inducing cracks and micro-channelsto further facilitate effectiveness of valvuloplasty. Use of therapeuticdrugs to treat stenosis and restenosis of heart valves may also beadvantageous for a better longer term clinical results.

FIG. 16A illustrates an aortic valve having diseased leaflets 1600, leftventricular outflow track 1601, valve annulus 1602, aortic sinus 1603,and aortic wall 1604. An ultrasound catheter 902 having a radiopaquemarker 905, a transmission member 903 and a distal tip 904 as shown inFIG. 14 is positioned within the diseased heart valve leaflets 1600.Ultrasound energy in form of radial waves 908 is delivered from thetransmission member 903 to the leaflets 1600, causing change incompliance by inducing micro-channels and micro-cracks in both stenotictissue and in calcifications. This improves the effect of aorticvalvuloplasty, and increases the permeability of the leaflets 1600. Theduration of ultrasound exposure should be greater than 1 second and notto exceed 60 minutes. The ultrasound catheter 902 is usually introducedto the treatment area through a femoral or brachial artery over aguidewire (not shown) using techniques that are well known in the art.

FIG. 16B illustrates an aortic valvuloplasty catheter 1605 having acatheter shaft 1606, an aortic dilatation balloon 1607, and a distal tip1608. The catheter 1605 is introduced through the same femoral orbrachial artery (not shown) over a guidewire 1609. As the balloon 1607is inflated with contrast media, the leaflets 1600 are pressed againstthe wall of aortic sinus 1603. It may be necessary to inflate anddeflate the aortic balloon 1607 several times to achieve the desiredflexibility in the valve leaflets 1600. Application of ultrasound energyto the leaflets maybe done prior to performing valvuloplasty, or aftervalvuloplasty. Examples of aortic balloons include but are not limitedto the V8™ Aortic Valvuloplasty Balloon Catheter (InterValve Inc.Minnetonka. Minn.).

FIG. 16C illustrates a dual balloon occlusion catheter 1610 having acatheter shaft 1611, two compliant balloons 1612A and 1612B, and adistal tip 1613. The catheter 1610 is positioned over the guidewire 1614between the heart valve leaflets 1600. The dual balloon catheter 1610provides protection during delivery of antistenotic drugs, so thattherapeutic drug does not flow down the blood stream, but is applied tothe leaflets 1600. The dual balloon catheter 1610 also has a distalshaft 1615 located between the balloons 1612A and 1612B. A drug outlet1616 is situated on the distal shaft 1615 and serves to delivertherapeutic agents into the space between the balloons 1612A and 1612B.Therapeutic drug 1617 delivered through the outlet 1616 is applied tothe valve leaflets 1600. The therapeutic drug 1617 is delivered underpressure from the outlet 1616 into the space between the balloons 1612Aand 1612B, causing the valve leaflets 1600 to open and be fully exposedto the therapeutic drug 1617. The therapeutic drugs should be applied tothe valve leaflets for a duration ranging between 1 second and 60minutes. An example of a dual balloon catheter that can be used herewithmay include but is not limited to the TAPAS™ Catheter (SpectraneticsCorp., Colorado Springs. USA).

If needed, prior to the steps described in FIGS. 16A, B, C, the tip 904can be used to decalcify the surface of the leaflets 1600 byrepositioning the ultrasound catheter 902 and the transmission member903 to a desired treatment location and performing calcification removal(e.g., by ablation). An additional sheath may be used around theultrasound catheter 902 to aspirate any particles created by ablation ofcalcific and non-calcific tissue from the leaflets.

Also the scope of the invention incorporates delivery of ultrasoundenergy to the vessel wall before, during and after delivery of thetherapeutic agent. Drug delivery may be achieved using ultrasound drugdelivery catheters or any separate drug delivery device. Drug deliverymay also be achieved with intravenous drug delivery or with endovascularmethods using ultrasound drug delivery catheters or any separate drugdelivery device.

To achieve the required therapy effects, it is desirable to applyultrasound energy while most of the therapeutic drug is still present atthe treatment area. If the therapeutic drug is delivered first, it wouldbe advantageous to deliver ultrasound energy to the treatment areawithin a short period of time after the drug has been applied. Ifultrasound energy is delivered first to the treatment area, the effectof ultrasound to enhance drug permeability lasts from the time whenenergy is delivered, and is usually no longer than 60 minutes afterultrasound energy is exposed to the vessel wall.

Other alternative embodiments of devices and methods for the presentinvention include delivery of the therapeutic drug intravenously (IV)and enhancing permeability of the vessel wall via the delivery ofultrasound energy to the treatment location. Ultrasound energy deliverywill induce local vasodilatation and sonoporation within the surroundingtissue, further increasing drug uptake. Ultrasound energy may be emittedto the treatment area using transcutaneous (from outside of the body) orendovascular catheter methods. IV delivery of drug will cause a systemiceffect causing the entire blood system to carry the therapeutic drug. Byusing a targeted ultrasound energy that is limited to a specifictreatment area, the applied drug penetrates into the vessel wall of thetreatment area more effectively. Emission of ultrasound energy and IVdelivery of the therapeutic drugs can be administered in a variety ofcombinations: the therapeutic drug may be delivered intravenously eitherbefore delivery of ultrasound energy to the treatment area, duringdelivery of ultrasound energy or after delivery of ultrasound energy tothe treatment area. In addition, a treatment area may be exposed to anyother interventional procedure, including but not limited to: balloonangioplasty or venoplasty, stent placement, atherectomy, laserprocedure, cryoplasty, other drug delivery and any combination of suchprocedures. Any interventional procedure may take place either before,during or after ultrasound/drug therapy. Further enhancement of thetherapeutic drug uptake in the treatment area may be achieved usingdistal, proximal or dual flow protection or flow limitation devices suchas compliant or non-compliant balloon devices. Therapeutic drug(s)delivered through the IV approach may be mixed with a conventionalsaline or any suitable contrast medium.

Still other alternative embodiments of devices and methods of theinvention include delivery of ultrasound energy to a treatment area anddelivery of therapeutic agent(s) that are mixed with a suitable contrastmedium. The concept of using contrast media as a matrix forantiproliferative drugs delivery can simply employ standard endovascularangiography techniques. The contrast medium is chosen as the vehicle fortherapeutic drug delivery because it significantly enhances thesolubility of the drugs that are usually not easily solvent inconventional saline. Examples of suitable contrast medium include butare not limited to: Omnipaque 300, Amersham Health, NJ, USA;Ultravist-300, Schering AG. Berlin, Germany and NIOPAM 300, Bracco UKLimited. Ultrasound energy delivery will induce local vasodilatation andsonoporation within the vessel wall, further increasing permeability ofthe drug delivered with contrast medium. Ultrasound energy may bedelivered to the treatment area using transcutaneous methods (fromoutside the body) or endovascular catheter methods. Delivery oftherapeutic drugs to the treatment area can be administered in a varietyof combinations: therapeutic drug may be delivered either beforedelivery of ultrasound energy to the treatment area, during delivery ofultrasound energy to the treatment area, or after delivery of ultrasoundenergy to the treatment area. Therapeutic drug may be delivered by theultrasound catheter that is energized or not energized, by a separatedrug delivery catheter or through a conventional medium injection into apercutaneous sheath. In addition, a treatment area may be exposed to anyother interventional procedure including but not limited to: balloonangioplasty or venoplasty, stent placement, atherectomy, laserprocedure, ultrasound angioplasty or venoplasty, cryoplasty, other drugdelivery and any combination of such procedures. Any interventionalprocedure may take place either before, during or after ultrasound/drugtherapy. Further enhancement of the therapeutic drug uptake in thetreatment area may be achieved using distal, proximal or dual flowprotection or flow limitation devices, such as for example, compliant ornon-compliant balloon devices.

Another embodiment of the present invention includes delivery ofultrasound energy to a treatment area and delivery of therapeuticagent(s) that are mixed with Carbamide. Carbamide is an organic compoundwith the chemical formula (NH₂)₂CO. The molecule has two amine (—NH₂)groups joined by a carbonyl (C═O) functional group, and is also known asurea. Urea serves an important role in the metabolism ofnitrogen-containing compounds by animals and is the mainnitrogen-containing substance in the urine of mammals. It is solid,colourless, and odorless. It is highly soluble in water and non-toxic.Dissolved in water, it is neither acidic nor alkaline. The body uses itin many processes, most notably nitrogen excretion. Carbamide can besynthesized in the lab without biological materials. It has beenhypothesized that Carbamide may be a good and effective solvent todilute Paclitaxel for use in anticancer and antistenosis therapy.

While the ultrasound delivery methods above describe transcutaneoustransducers that are located outside the body (for example, U.S. Pat.No. 6,398,772 (Bond et al.)) and endovascular transducers located on theproximal end of the catheter (for example, U.S. Pat. No. 5,342,292 (Nitaet al.)), use of small endovascular transducers located at the distalend of the catheter is also possible. Examples of such distaltransducers are illustrated in U.S. Pat. No. 5,728,062 (Brisken). U.S.Pat. No. 6,001,069 (Tachibana et al.), U.S. Pat. No. 6,372,498 (Newmanet al.). U.S. Pat. No. 6,387,116 (McKenzie et al.), U.S. Pat. No.6,432,068 (Corl et al.), U.S. Pat. No. 6,484,052 (Visuri et al.), andU.S. Pat. No. 6,723,063 (Zhang et al.), and these disclosures are herebyincorporated by this reference as though set forth fully herein. The useof ultrasound energy to disrupt clots and to enhance delivery of drugsto clots has been recently proposed using a flexible probe, where theentire length of the probe forms a cutting surface to ablate unwantedtissue in the transverse mode of operation. Examples of such flexibleprobes are illustrated in U.S. Pat. Nos. 6,551,337, 6,652,547 and7,494,468, which solely relays transverse motions of the flexible probe,and these disclosures are hereby incorporated by this reference asthough set forth fully herein.

The development of thrombosis as a result of vessel injury or delayedendothelialization is a recognized risk of transcutaneous orendovascular intervention with some therapeutic agents that may be usedto prevent restenosis. In such cases, administration of the appropriatemedication may be required.

Ultrasound energy delivered for stenosis and restenosis therapies eitherin endovascular or transcutaneous fashion may be generated or producedby longitudinal sound waves, transverse sound waves, radial sound waves,or combination of these sound waves.

Although the invention has been described above with respect to certainembodiments, it will be appreciated that various changes, modifications,deletions and alterations may be made to such above-describedembodiments without departing from the spirit and scope of theinvention. Accordingly, it is intended that all such changes,modifications, additions and deletions be incorporated into the scope ofthe following claims. More specifically, description and examples havebeen provided that relate to treatment of stenotic arterial sites and totherapeutic agents that are appropriate for treating such sites.However, the scope of the invention includes the application of thesemethods to treating sites other than stenotic sites, and to facilitatingthe intracellular delivery of any therapeutic agent appropriate fortreating the particular target site.

Some theoretical considerations have been provided as to the mechanismby which these therapeutic methods are effective; these considerationshave been provided only for the purpose of conveying an understanding ofthe invention, and have no relevance to or bearing on claims made tothis invention.

The invention claimed is:
 1. A vibrational system for treatingendovascular disease of a patient, comprising: a signal generator thatis capable of producing a signal at a frequency of 1 KHZ-10 MHZ and apower of less than 20 Watts, wherein the signal generator is configuredto produce the signal in each of: (i) a continuous mode, whereuponoperating in the continuous mode, the signal generator continuouslyproduces ultrasound energy; (ii) a pulse mode, whereupon operating inthe pulse mode, the signal generator produces ultrasound energy inpulses; and (iii) a modulated mode, whereupon operating in the modulatedmode, the signal generator produces ultrasound energy in pulses andmodulates the pulses to have varying pulse parameters; a transducercoupled to the signal generator to convert the signal produced by thesignal generator to vibrational energy; an elongated ultrasoundtransmission member having a distal end configured to be inserted intothe body of the patient, and a proximal end coupled to the transducer,wherein the elongated ultrasound transmission member is configured topropagate the vibrational energy received from the transducer at theproximal end of the transmission member through the transmission memberto the distal end of the transmission member; and a catheter having anirrigation lumen and an irrigation port in fluid communication with theirrigation lumen, wherein the catheter at least partially surrounds theultrasound transmission member and is axially aligned proximally of thedistal end of the elongated ultrasound transmission member to direct thesurface waves from the distal portion of the transmission member towarda treatment area, wherein the irrigation port discharges an irrigationfluid through at least one outflow channel at the distal end of thecatheter, and wherein the vibrational energy received from thetransducer propagates toward the treatment area as the surface waves inthe irrigation fluid discharged from the catheter; wherein an anchormember is attached to the distal end and the ultrasound transmissionmember; and wherein the distal end of the elongated transmission memberextends outside of the catheter, and the system further includes apolymer sheath positioned along the distal end of the ultrasoundtransmission member and the anchor member, the polymer sheath having asmaller diameter than the catheter.
 2. The system of claim 1, whereinthe signal generator is an extracorporeal device.
 3. The system of claim1, wherein a polymer shell is positioned around the distal end of theultrasound transmission member and is at least partially surrounding aradiopaque marker of the elongated ultrasound transmission member, theanchor member, and the ultrasound transmission member.
 4. The system ofclaim 1, wherein a separate tip is attached on the distal end of theultrasound transmission member.
 5. The system of claim 4, wherein theanchor member is attached to the separate tip.
 6. The system of claim 5,further including a radiopaque marker positioned on the ultrasoundtransmission member.
 7. The system of claim 6, wherein a polymer shellis at least partially surrounding the ultrasound transmission member. 8.The system of claim 1, wherein a radiopaque marker is attached to thedistal end of the catheter.
 9. The system of claim 1, wherein thecatheter includes a guidewire lumen.
 10. The system of claim 1, whereinthe catheter is configurable to be repositioned along the ultrasoundtransmission member.
 11. The system of claim 1, wherein the ultrasoundtransmission member is connected at its proximal end to a sonicconnector, wherein the ultrasound transmission member is surrounded byone or more absorbers positioned around the proximal end of theultrasound transmission member.